BakerIDI Student Research Projects 2017

STUDENT RESEARCH PROJECTS
2017
Addressing the changing health

landscape
1927 - 2017
Baker IDI Heart and Diabetes Institute is an

independent, internationally-renowned medical
research facility, with a history spanning more than
89 years. The Institute's work extends from the
laboratory to wide-scale community studies with a
focus on diagnosis, prevention and treatment of
diabetes and cardiovascular disease.
The comprehensive range of research undertaken
to target these deadly diseases, combined with the
flexibility and innovation to respond to changing
health and community needs, is unique and sets
Baker IDI apart from other health and research
Institutes.
The Institute's mission is to reduce death and
disability from cardiovascular disease, diabetes and
related disorders; two prevalent and complex
diseases responsible for the most deaths and the
highest health costs in the world.
With Australia facing an ageing population and
rapidly growing rates of chronic disease, Baker IDI's
work has never been more important to Australian
communities, as well as the global communities in which it operates.
Baker IDI is well positioned to address these challenges. The Institute's highly diverse team
includes cardiologists, diabetes physicians, bench-top scientists, epidemiologists, dietitians,
psychologists, nurse educators, renal specialists and physical activity experts. Together, they are
working to translate laboratory findings into new approaches to prevention, treatment and care.
The Institute's main laboratory facilities are located on the Alfred Medical Research and Education
Precinct in Melbourne, Victoria. Baker IDI also has a research facility in Alice Springs in the
Northern Territory dedicated to Indigenous health. In keeping with a global research agenda, the
Institute maintains international partnerships and collaborations in Europe, North America, the
Middle East, South Africa and the Pacific.
For enquiries relating to research projects for 2017 contact details for lab
heads are provided with the offered projects
Project title: Does renal dopamine help or hinder diabetic kidney disease?
Laboratory: Diabetic Complications & the Kidney
Primary Supervisor :Dr. Anna Watson
Contact:
Anna.Watson@bakeridi.edu.au
Research Focus:
Diabetic Kidney disease, sympathetic nerves
8532 1455
Keywords
Diabetes, nerves, kidney, dopamine, noradrenaline
Project description:
Diabetes is typified by increases in blood glucose which leads to increased urine production. Renal
sympathetic nerves, as well as renal dopamine produced by renal tubules help control urine production
and reabsorption of solutes, including glucose and sodium. The integration of renal sympathetic nerve
signaling and the intrarenal dopaminergic system is poorly understood, especially in the context of
diabetes. This laboratory has established changes in levels of both renal dopamine and neurally derived
noradrenaline in the kidney of diabetic mice.
This project aims to examine the effect of dopamine production in renal proximal tubule cells in vitro in a
diabetic environment, with and without the addition of noradrenaline. The results of this project will help
determine whether renal dopamine production is changed by the diabetic environment and whether
sympathetic neurotransmission (via noradrenaline) helps or hinders this. The results of this project with
help to establish how these two important mediators of fluid balance interact as well as how diabetes
impacts upon this.
Project related methods/skills/technologies:

Cell culture
qPCR
Immunohistochemistry
Western blot
ELISA
References:
1. Zhang, MZ, Yao, B, Yang, S, Yang, H, Wang, S, Fan, X, et al., Intrarenal dopamine inhibits progression of diabetic
nephropathy. Diabetes 2012;61:2575-2584
2. Murabayashi, S, Baba, T, Tomiyama, T and Takebe, K, Urinary dopamine, noradrenaline and adrenaline in type 2
diabetic patients with and without nephropathy. Hormone and metabolic research 1989;21:27-32
3. Rafiq, K, Fujisawa, Y, Sherajee, SJ, Rahman, A, Sufiun, A, Kobori, H, et al., Role of the renal sympathetic nerve in
renal glucose metabolism during the development of type 2 diabetes in rats. Diabetologia 2015;58:2885-2898
Project title:
Do diabetes and hypertension contribute to changes in the control of the sympathetic nervous system?
Laboratory: Diabetic Complications/Neuropharmacology
Primary Supervisor (s): Dr. Anna Watson, Dr Pam Davern
Contact:
Anna.Watson@bakeridi.edu.au
Research Focus:
Diabetic complications/ autonomic neurobiology
8532 1455
Keywords
Nerves, brain, sympathetic nerves, mouse models
Patients with diabetes often also have hypertension and these patients are also more likely to develop
kidney disease than patients who have either condition alone. This is often marked by increases in global
sympathetic nerve activity, thought to be perpetuated by afferent nerve feedback from the diseased
kidney. We have previously established that areas of the brain associated with sympathetic outflow are
altered in hypertension. We have also established that mice with both diabetes and hypertension show
changes in the quantity and location of neurotransmitters in the kidney differentially to mice that have
either condition alone. The effect of having diabetes and hypertension concomitantly has never been
investigated in the brain however.
This project aims to examine whether the brain areas associated with sympathetic nerve activity also
undergo alteration by assessing changes in neurotransmission in diabetic and hypertensive mice. This
project will involve assessment of neurotransmitters by gene analysis (PCR) as well as assessment of
changes in location and quantity of neurotransmitters (immunohistochemistry and Western blot).
Ultimately this information will lead to a better understanding of how changes in the brain contribute or
attenuate the development of diabetic complications.

qPCR
Histology
ELISA
Western blot
References:
1. Jackson, K. L., F. Z. Marques, A. M. Watson, K. Palma-Rigo, T. P. Nguyen-Huu, B. J. Morris, F. J. Charchar, P. J. Davern

and G. A. Head (2013). "A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR181a in BPH/2J genetically hypertensive mice." Hypertension 62(4): 775-781.
2. Davern, P. J., K. L. Jackson, T. P. Nguyen-Huu, L. La Greca and G. A. Head (2010). "Cardiovascular reactivity and
neuronal activation to stress in Schlager genetically hypertensive mice." Neuroscience 170(2): 551-558.
3. Zheng, H., X. Liu, Y. Li, P. K. Mishra and K. P. Patel (2013). "Attenuated dopaminergic tone in the paraventricular
nucleus contributing to sympathoexcitation in rats with Type 2 diabetes." Am J Physiol Regul Integr Comp Physiol
306(2): R138-148.
Project title: The role of prooxidant enzyme Nox5 in diabetic kidney disease
Laboratory: Diabetic Complications (Diabetes and Kidney Disease)
Primary Supervisor (s): Prof. Karin Jandeleit-Dahm & Dr. Jay C Jha
Contact: Jaychandra.jha @bakeridi.edu.au
Phone: 8532 1565
Research Focus: To identify Nox5 as a novel therapeutic target for the prevention and treatment of
diabetes related kidney failure.
Keywords: Diabetes, diabetic nephropathy, reactive oxygen species (ROS), Glomerulosclerosis
The development of diabetic complications including vascular and renal disease is enhanced in diabetic
patients. However, the underlying mechanism as to why this disease process is accelerated is largely
unknown. Oxidative stress has been proposed to play a key role in the development of diabetic
complications including diabetic nephropathy, particularly the NADPH oxidase (Nox) family. There are
primarily 4 Nox isoforms that have been shown to be important in the development of diabetic
complications, Nox1, 2, 4 and 5. All of these isoforms have increased expression and activity in diabetic
patients. Our group has established a role for the Nox1 isoform in the development of diabetic
atherosclerosis, and the Nox4 isoform in diabetic kidney disease. However, to date a role for the Nox5
isoform in diabetic complications is unknown.
This project will mainly focus on the role of Nox5 in the development and progression of diabetic
nephropathy. The projects will utilize a highly novel humanised Nox5 knockin mouse, where Nox5 is
expressed in the renal cells. The experimental end point will be to assess the renal function, albuminuria,
renal structural injuries (glomerulosclerosis and tubulointerstitial fibrosis) as well as markers of fibrosis
and inflammation.

The project will involve applying various experimental techniques that include
Immunohistochemistry & Western Blot for protein expression analysis
Real time- PCR for gene expression analysis
Measurement of renal function
Cell culture
References:
1. Jha, J.C., et al., Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in
Long-Term Diabetic Nephropathy. J Am Soc Nephrol, 2014.
2. Gray SP., et al. Nox1 plays a key role in diabetes associated atherosclerosis Circulation. 2013
3. Guzik TJ., et al. Calcium-dependent nox5 nicotinamide adenine dinucleotide phosphate oxidase contributes to
vascular oxidative stress in human coronary artery disease. J Am Coll Cardiol. 2008
4. Montezano AC., et al. Nicotinamide adenine dinucleotide phosphate reduced oxidase 5 (nox5) regulations by
angiotensin ii and endothelin-1 is mediated via calcium/calmodulin-dependent, rac-1-independent pathways in human
endothelial cells. Circ Res. 2010.
Project title: Investigating pathways of mitochondrial quality control in diabetic kidney disease
Laboratory: Glycation, Nutrition & Metabolism
Primary Supervisor (s): A/Prof Melinda Coughlan & Dr Gavin Higgins
Contact:
gavin.higgins@bakeridi.edu.au
8532 1503
Research Focus: Diabetic nephropathy, mitochondrial dysfunction

Keywords Diabetic nephropathy, renal disease, mitochondria
Diabetic nephropathy (DN) is a progressive microvascular complication arising from diabetes. Within the
kidney, the glomeruli, tubules, vessels and interstitium are disrupted, ultimately impairing renal function,
and leading to end stage renal disease (ESRD) and death. Current therapies used in individuals with DN do
not prevent the inevitable progression to ESRD, therefore new targets of therapy are urgently required.
Studies from animal models indicate that disturbances in mitochondrial homeostasis are central to the
pathogenesis of DN. Since renal proximal tubule epithelial cells (PTECs) rely on oxidative phosphorylation
to provide adequate ATP for tubular reabsorption, an impairment of mitochondrial bioenergetics in this
cell type results in renal functional decline. Accumulation of damaged mitochondria are found in the renal
cortex in animals with DN, suggesting that mitochondrial clearance mechanisms may be impaired.
In order to maintain a pool of functional mitochondria, cells have a housekeeping process called
autophagy, which selectively removes damaged proteins and organelles. The process of removing
damaged mitochondria is termed mitophagy. In diabetic nephropathy the accumulation of damaged
mitochondria is thought to contribute to its pathology. The aim of this project will be to understand how
mitochondrial quality control pathways are altered in diabetic kidney disease.
Research question: Does mitophagy impairment contribute to the development and/or progression of
diabetic nephropathy?
To establish which stressors within the diabetic milieu impact on changes in autophagic flux, experiments
on live human renal cells in a diabetes-like environment will be carried out in vitro. Agents that inhibit or
induce autophagy activity will be used in order to help characterise the autophagic response.
Project suitable for Honours 2017

Confocal microscopy (see image above), incorporating immunocytochemical techniques.
Western immunobloting.
Fluorogenic and colorimetric enzyme activity assays using scanning plate reader.
Tali Image based cytometer for cell counting.
Cell culturing of human PTECs.
Assessment of mitochondrial morphology (using electron microscopy) and bioenergetics (using
the Seahorse bioanalyser).
References:
1. Higgins, G.C. and Coughlan, M.T. (2014) Mitochondrial dysfunction and mitophagy: The beginning and end to
diabetic nephropathy? Br J. Pharmacol 171(8):1917-42
2. Jin, S.M. and Youle, R.J. (2012) PINK1 and Parkin mediated autophagy at a glance, J Cell Sci (125): pp. 795-799.
3. Feng, D., Liu L, Zhu, Y. and Chen, Q. (2013) Molecular signalling toward mitophagy and its physiological
significance, Exp Cell Res (319)12: pp. 1697-705.
4. Forbes, J.M. and Cooper M.E. (2013) Mechanisms of Diabetic Complications, Physiol Rev 93: pp. 137-188.
Project title: The role of let 7 micro-RNA in atherosclerosis: endothelial cells
Laboratory: Genes and Diabetes (Diabetic Complications Laboratory)

Primary Supervisor (s): Phillip Kantharidis
Contact: Phillip Kantharidis
Phillip.kantharidis@bakeridi.edu.au
Research Focus:
Diabetes associated atherosclerosis
8532 1462
Keywords
microRNA, atherosclerosis, endothelial cells, inflammation
Patients with diabetes have mortality from cardiovascular disease that is over twice that observed in the
general population, resulting in atherosclerotic plaque formation. The diabetic plaque is characterized by
macrophage accumulation and abnormalities in both aortic endothelial and vascular smooth muscle cell
function. Within the atherosclerotic cytokine network, tumor necrosis factor-alpha (TNF-alpha) is
implicated as a key molecular driver. Our data in vascular smooth muscle cells suggests that the let-7
micro-RNA family may have an important role in the pathogenesis of the diabetic plaque, with TNF-alpha
down regulating the expression of this miRNA family. Restoring the expression of let-7 miRNAs in vascular
smooth muscle cells can attenuate TNF-alpha-mediated signaling. However, the impact of restoring let-7
expression in aortic endothelial cells and macrophages is unclear. This project will investigate whether
restoring let-7 miRNA levels in primary mouse aortic endothelial cells and macrophages can suppress
inflammatory signals mediated by TNF-alpha. The project will involve the use of transfection techniques
but also the use of novel therapeutic compounds to attenuate the effect of TNF and hence
atherosclerosis.
Animal experiments
Tissue culture
Transfection with miRNA mimics
rtQ-PCR analysis for gene and microRNA expression
Western analysis
NFkB reporter gene assays
Monocyte adhesion assays
Animal tissue handling, processing and analysis
References:
1. Wang B, Jha JC, Hagiwara S, McClelland AD, Jandeleit-Dahm K, Thomas MC, Cooper ME, Kantharidis P:
Transforming growth factor-beta1-mediated renal fibrosis is dependent on the regulation of transforming growth
factor receptor 1 expression by let-7b. Kidney international 2014, 85:352-61.
2. McClelland AD, Kantharidis P: microRNA in the development of diabetic complications. Clinical science 2014,
126:95-110.
3. Hagiwara S, Kantharidis P, Cooper ME: MicroRNA as biomarkers and regulator of cardiovascular development and
disease. Current pharmaceutical design 2014, 20:2347-70.
Project title: RNA biomarkers predictive of patients at risk of developing diabetic nephropathy

Research Focus:
Biomarkers for diabetic nephropathy
8532 1462
Keywords
microRNA, biomarkers, RNA-seq, bioinformatics
Not all patients with diabetes are at risk of also developing complications such as end stage kidney disease
and diabetes associated atherosclerosis. Approximately 30 % of patients develop these debilitating
conditions. Despite the research to date we do not have any good means of identifying patients at risk of
developing complications. In terms of the kidney, diabetic nephropathy is the most common cause of
chronic kidney disease in people with diabetes. This condition is characterized by glomerular changes such
as glomerular basement thickening, mesangial expansion, renal hypertrophy and the accumulation of
extracellular matrix (ECM) proteins. These changes are largely driven by TGF- which stimulates ECM
production in many cell types.
The aim of this project is to use RNA-seq techniques to identify RNA biomarkers in urine from control and
diabetic patients which not only are diagnostic of disease, but more importantly may be able to predict
disease development. Archival and fresh samples will be used to identify RNA (mRNA and miRNA)
biomarkers and these will be then be tested against a panel of samples from patients whose history is
known. Potential biomarkers will be further assessed in terms of relevance to disease using in vitro assays
and animal models of diabetic nephropathy.
RNA isolation techniques

RNA-seq and bioinformatics
Tissue culture
Transfection with miRs
rtQ-PCR analysis
western analysis
References:
1. Hagiwara S, Kantharidis P, Cooper ME: MicroRNA as biomarkers and regulator of cardiovascular development and
disease. Current pharmaceutical design 2014, 20:2347-70.
3. Wang B, Komers R, Carew R, Winbanks CE, Xu B, Herman-Edelstein M, Koh P, Thomas M, Jandeleit-Dahm K,
Gregorevic P, Cooper ME, Kantharidis P: Suppression of microRNA-29 expression by TGF-beta1 promotes collagen
expression and renal fibrosis. Journal of the American Society of Nephrology : JASN 2012, 23:252-65.
4. Wang B, Koh P, Winbanks C, Coughlan MT, McClelland A, Watson A, Jandeleit-Dahm K, Burns WC, Thomas MC,
Cooper ME, Kantharidis P: miR-200a Prevents renal fibrogenesis through repression of TGF-beta2 expression.
Diabetes 2011, 60:280-7.
5. Wang B, Herman-Edelstein M, Koh P, Burns W, Jandeleit-Dahm K, Watson A, Saleem M, Goodall GJ, Twigg SM,
Cooper ME, Kantharidis P: E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of
the profibrotic effects of transforming growth factor-beta. Diabetes 2010, 59:1794-802.
Project title: Lipoxin A4 analogues as a treatment for diabetic nephropathy

Research Focus:
Biomarkers for diabetic nephropathy
8532 1462
Keywords
Inflammation, microRNA, diabetic nephropathy
Diabetic nephropathy (DN) is the most common cause of chronic kidney disease in people with diabetes.
The major characteristics of DN include glomerular basement thickening, mesangial expansion, renal
hypertrophy and the accumulation of extracellular matrix (ECM) proteins. TGF- is the most potent
inducer of renal fibrosis because it stimulates ECM production in many cell types, but because it also
transformed cells to a profibrotic phenotype, inducing the expression of other fibrogenic molecules (eg.
CTGF), thus amplifying the effect of TGF-. Many fibrogenic mechanisms appear to converge on TGF- and
its receptors to signal through the SMADs, MAPKs and other pathways. The role of altered expression of
certain miRNAs in TGF treated proximal tubular cells appears to contribute to the increased expression
of ECM proteins (collagens, fibronectin, SMA, etc). Restoring the expression of some of these miRs can
attenuate the effects of TGF in terms of ECM synthesis.
However, the direct targeting of TGF- as an anti-fibrotic treatment has been problematic because of the
critical role this factor plays in immune surveillance. We have found that a family of naturally occurring
molecules in the body (lipoxins) have the ability to modulate TGF signaling and restore the expression of
certain miRNAs that contribute to renal disease, and hence are able to reduce the damage caused by
diabetes in the kidney. Access to newly designed stable analogues of these compounds provides us with a
unique opportunity to test new treatments against diabetic nephropathy.
Animal experiments
RNA isolation techniques
rtQ-PCR (gene expression) analyses
Tissue culture
Transfection with miRs
western analyses
mitochondrial and oxidative stress assays
References:
2. Wang B, Komers R, Carew R, Winbanks CE, Xu B, Herman-Edelstein M, Koh P, Thomas M, Jandeleit-Dahm K,
Gregorevic P, Cooper ME, Kantharidis P: Suppression of microRNA-29 expression by TGF-beta1 promotes collagen
expression and renal fibrosis. Journal of the American Society of Nephrology : JASN 2012, 23:252-65.
3. Wang B, Koh P, Winbanks C, Coughlan MT, McClelland A, Watson A, Jandeleit-Dahm K, Burns WC, Thomas MC,
Cooper ME, Kantharidis P: miR-200a Prevents renal fibrogenesis through repression of TGF-beta2 expression.
Diabetes 2011, 60:280-7.
4. Wang B, Herman-Edelstein M, Koh P, Burns W, Jandeleit-Dahm K, Watson A, Saleem M, Goodall GJ, Twigg SM,
Cooper ME, Kantharidis P: E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of
the profibrotic effects of transforming growth factor-beta. Diabetes 2010, 59:1794-802.
Project title: Investigating the role of IL18 and its natural inhibitor IL18bp in type 2 diabetes and obesity
Laboratory: Haematopoiesis and Leukocyte Biology Laboratory
Primary Supervisor (s): Dr Helene Kammoun / Dr Andrew Murphy
Contact:
Helene.kammoun@bakeridi.edu.au
8532 1424
Andrew.murphy@bakeridi.edu.au
8532 1292
Research Focus: IL-18 signalling in obesity and diabetes
Keywords: Obesity, diabetes, inflammation, interleukin 18
The incidence of obesity has increased dramatically in recent decades. The World Health Organization has
estimated that in excess of 1 billion people worldwide are overweight, with 300 million defined as
clinically obese. Obesity is associated with a wide range of disorders including insulin resistance, type 2
diabetes, atherosclerosis and cancer. One cytokine implicated in regulating systemic energy homeostasis
is IL-18. IL-18 has profound anti-obesity effects demonstrated convincingly in mice, where injection of IL18 prevents weight gain, and loss of IL-18 results in exacerbated adiposity and insulin resistance by 6
months of age. In the human population, a common IL-18 haplotype is associated with decreased IL-18
expression and increased BMI for individuals with type 2 diabetes however obese patients develop IL-18
resistance and present high levels of circulating IL-18 unable to signal its beneficial metabolic effects.
IL-18binding protein (IL-18bp) is an endogenous negative regulator of IL18 secreted mainly by cells of the
immune system. We hypothesise that IL-18bp deficient mice should have increased IL-18 signalling, and
thus less adipose tissue mass.
To know more about the role of IL-18 signalling in metabolism, we will use knock-out mouse models as
well as bone marrow transplant techniques in mice on a high fat diet. We plan to investigate a whole body
or immune cell-restricted genetic inhibition of IL-18bp in order to restore IL-18 signaling in a mouse model
of insulin resistance and type 2 diabetes. We expect to see a decreased adiposity and improved glucose
tolerance in these animals. We also will aim to confirm these genetic findings using a pharmacological
approach. We will treat the obese mice with a neutralizing antibody directed against IL-18bp and will
develop an IL-18bp small molecule inhibitor using screening techniques. The inhibition of IL18bp could
represent a strong therapeutic target for obesity and diabetes.
Flow cytometry
RT-PCR
Animal models (mice on High fat diet)
ELISA
References:
1. Netea, M.G., et al., Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin
resistance. Nat Med, 2006. 12(6): p. 650-6.
2.
Zorrilla, E.P., et al., Interleukin-18 controls energy homeostasis by suppressing appetite and feed
efficiency. Proc Natl Acad Sci U S A, 2007. 104(26): p. 11097-102.
3.
Murphy, A.J., et al., IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and
Metabolic Syndrome. Cell Metab, 2016. 23(1): p. 155-64
10
Project title: The role of the parasympathetic nervous system in regulating hematopoiesis.
Primary Supervisor: Dr Andrew Murphy
Contact: Andrew.murphy@bakeridi.edu.au
8532 1292
Research Focus: Parasympathetic signaling and hematopoiesis in cardiovascular disease
Keywords: Haematopoiesis, Hematopoietic stem cells, atherosclerosis
Cardiovascular disease (CVD) is the leading cause of death worldwide. Atherosclerosis, a chronic
inflammatory disease of the arterial wall is the main contributor of this disease. This process begins with excess
cholesterol depositing into the arterial wall, which recruits circulating monocytes into the sub-endothelial
space where they differentiate into macrophages and engulf cholesterol. Upstream of this process we have
discovered an important role of the haematopoietic system, there circulating blood cells are produced, in providing enhanced
numbers of monocytes to drive atherosclerotic lesion progression.
We have recently discovered a novel role for the parasympathetic nervous system (PSNS) in the regulation
of haematopoiesis. We are particularly interested in how the PSNS interacts to regulate the production of
monocytes and neutrophils and the impact on cardiovascular disease.
The aims of this project are to elucidate the role for the PSNS in modulating haematopoiesis. We are
particularly interested in how the PSNS effects the production of neutrophils and monocytes. We will take
a number of approaches, both pharmacological and genetic to inhibit or stimulate the PSNS. This will be
applied in models of atherosclerosis and possible down stream complication such as stroke or myocardial
infarction.
Flow cytometry
RT-PCR
Animal models of disease
ELISA
References:
1. Westerterp M*, Gourion-Arsiquaud S*, Murphy AJ*, Shih A, Cremers S, Levine RL, Tall AR and YvanCharvet L. Regulation of hematopoietic stem and progenitor cell mobilization by cholesterol efflux
pathways. Cell Stem Cell. 2012;11:195-206. * Equal fist author
2. Murphy AJ, Akhtari M, Tolani S, Pagler T, Bijl N, Kuo CL, Wang M, Sanson M, Abramowicz S, Welch C,
Bochem AE, Kuivenhoven JA, Yvan-Charvet L and Tall AR. ApoE regulates hematopoietic stem cell
proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin
Invest. 2011;121:4138-49.
11
Project title: Understanding the energy pathways regulating monocyte subsets and their recruitment to
the atherosclerotic plaque
Primary Supervisor : Dr Andrew Murphy
Contact: Andrew.murphy@bakeridi.edu.au
8532 1292
Research Focus: The effects of atherosclerosis on energy metabolism in monocyte subsets.
Keywords: atherosclerosis, monocytes, energy metabolism
Cardiovascular disease (CVD) is the leading cause of death worldwide. Atherosclerosis, a chronic
inflammatory disease of the arterial wall is the main contributor of this disease. This process begins with
excess cholesterol depositing into the arterial wall which recruits circulating monocytes into the subendothelial space where they differentiate into macrophages and engulf cholesterol. When macrophages
become overloaded with cholesterol, they are unable to emigrate out of the vessel wall and thus become
trapped, contributing to the atherosclerotic plaque. There are three subpopulations of circulating blood
monocytes (classical CD14+, intermediate - CD14+/CD16+ & non- classical CD16+) and recent clinical
observations indicate that of these the non-classical subset is significantly elevated in patients with CVD.
Thus, targeting non-classical monocytes in circulation may hold key to regressing the atherosclerotic
plaque. New evidence now suggests that the energy status of immune cells in chronic inflammatory
diseases such as atherosclerosis plays a critical role and that manipulating their energy pathways may hold
the therapeutic key to the regression of atherosclerotic plaques. We have shown for the first time that
non-classical monocytes isolated from healthy blood donors meet their normal energy needs through
increased mitochondrial respiration compared to the classical and intermediate subset
(Figure). Whether their energy metabolism is altered after exposure to
high cholesterol or high glucose, as seen in atherosclerosis or
diabetes, remains to be determined. This project will involve the
use of an atherosclerotic mouse model to understand how the
metabolic requirements of monocyte subsets differ to healthy
control mice, and whether manipulating their energy pathways
may prevent them from entering the subendothelial wall and
feeding into the atherosclerotic plaque.

Flow cytometry
RT-PCR
Seahorse extracellular flux analyser
Transmigration assays
References:
1. Kelly B, O'Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015
Jul;25(7):771-84.
12
Project title: Circulating microRNAs as novel biomarkers for acute myocardial ischemia
Laboratory: Haematopoiesis and Leukocyte Biology
Primary Supervisor (s): Dr. Lu Fang, Associate Prof. Andrew Murphy, Prof. Anthony Dart
Contact:
KarenLu.Fang@bakeridi.edu.au
8532 1560
Research Focus:
We aim to evaluate circulating microRNAs as a rapid and sensitive marker for acute myocardial ischemia
Keywords: myocardial ischemia, microRNAs, biomarkers
Coronary artery disease and acute myocardial infarction (AMI) are the leading cause of death worldwide.
Over the last few decades, measurement of circulating biomarkers has become important in the diagnosis
of acute chest pain. Cardiac troponin, which rises at about 3.5 h after the onset of chest pain in AMI patients,
is a diagnostic marker for AMI. However, there are currently no rapid and easily assessed markers for acute
myocardial ischemia.
MiRNAs are short, noncoding RNAs of 18-25 nucleotides that posttranscriptionally control gene expression.1
Circulating miRNAs, released by cells into circulation, are potential novel biomarker for cardiovascular
diseases such as AMI, heart failure, and hypertension.2, 3 Recent studies suggest that circulating miRNAs rise
earlier than cardiac troponin. In animal models with AMI, circulating miRNAs elevated 15-30 min after
ischemia (insufficient to lead to cardiac cell death),4 suggesting that myocardial ischemia less than 15 min
may be a sufficient stimulus for cardiac release of miRNAs.
This project is aimed to study whether measurement of plasma miRNA profile, as a non-invasive method,
help to identify acute chest pain patients with ischemic heart disease from non-ischemic heart disease and
if so whether they will also identify the extent of myocardial ischemia.
We will take blood from chest pain patients referred to stress nuclear medicine imaging. Myocardial
ischemia will be diagnosed by stress nuclear perfusion test. Plasma miRNAs will be compared between
patients with chest pain due to ischemia or non-ischemia. The relation between miRNA levels and the
degree of ischemia will be assessed.
Recruiting patients with chest pain from Alfred Hospital and collect blood samples
Performing assays, such as isolating RNA from plasma samples, performing real-time PCR, Elisa
etc
Analyzing data and performing statistical tests
References:
Ono K, Kuwabara Y, Han J. MicroRNAs and cardiovascular diseases. FEBS J. 2011;278(10):1619-1633.
Tijsen AJ, Pinto YM, Creemers EE. Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases. Am J
Physiol Heart Circ Physiol. 2012;303(9):H1085-1095.
3.
Fichtlscherer S, Zeiher AM, Dimmeler S. Circulating microRNAs: biomarkers or mediators of cardiovascular diseases?
Arterioscler Thromb Vasc Biol. 2011;31(11):2383-2390.
4.
Li S, Zhu J, Zhang W, Chen Y, Zhang K, Popescu LM, Ma X, Lau WB, Rong R, Yu X, Wang B, Li Y, Xiao C, Zhang M, Wang S,
Yu L, Chen AF, Yang X, Cai J. Signature microRNA expression profile of essential hypertension and its novel link to human
cytomegalovirus infection. Circulation. 2011;124(2):175-184.
1.
2.
13
Project title: The role of phospholipids in macrophage polarization

Laboratory: Haematopoiesis and Leukocyte Biology
Primary Supervisor (s): Dr. Lu Fang, Associate Prof. Andrew Murphy
Contact:
KarenLu.Fang@bakeridi.edu.au
Research Focus:
The role of phospholipids and macrophage polarization
8532 1560
Keywords: macrophage polarization, phospholipids, inflammation

Macrophages play an important role in the initiation, development and instability of atherosclerotic
plaques. In the earliest stage of atherosclerosis, macrophages engulf oxidized low-density lipoprotein (LDL)
and become foam cells, which is the hallmark of atherosclerosis. Foam cells, in turn, contribute to
continuous recruitment of circulating monocytes, advancement of atherosclerosis and plaque vulnerability
by secreting a variety of pro-inflammatory cytokines, chemokines, and proteases. Macrophages can be
polarized with different stimuli into two distinct subsets: classically-activated (M1) macrophages and
alternatively-activated (M2) macrophages. M1 macrophages have pro-inflammatory phenotype and have
the capacity to sustain inflammation by secreting inflammatory cytokines. On the other hand, M2
macrophages are anti-inflammatory and promote tissue repair and healing. 1
Unlike LDL, high-density lipoprotein (HDL) has atheroprotective function and is inversely associated with
the risk of cardiovascular disease.2 HDL is known to exert atheroprotective action through promoting
reverse cholesterol transportation and inhibiting inflammatory response. While the majority studies on
HDL focus on Apo-A1, the protein component of HDL, there is accumulating evidence pointing to the
importance of lipid component of HDL. Phospholipids (PL) is a major lipid component of HDL.
Epidemiological studies have found that the severity of coronary artery disease is correlated with low
levels of HDL-PL.3 Several studies have also shown that PL of HDL plays a role in reverse cholesterol efflux.4
Our previous work has shown that PL promotes M2 but inhibits M1 macrophage polarization. Next, we
aim to further explore the signalling pathways by which PL mediates its actions.
Blood monocyte isolation and cell culture

Technique of cellular and molecular biology, such as flow cytometry, real-time PCR, Western blot,
cell imaging, etc
data analysis and statistical tests
References:
1.
2.
Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5(12):953-964.
Prospective Studies C, Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R.
Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61
prospective studies with 55,000 vascular deaths. Lancet. 2007;370(9602):1829-1839.
3.
Piperi C, Kalofoutis C, Papaevaggeliou D, Papapanagiotou A, Lekakis J, Kalofoutis A. The significance of serum HDL
phospholipid levels in angiographically defined coronary artery disease. Clin Biochem. 2004;37(5):377-381.
4.
Johnson WJ, Bamberger MJ, Latta RA, Rapp PE, Phillips MC, Rothblat GH. The bidirectional flux of cholesterol between
cells and lipoproteins. Effects of phospholipid depletion of high density lipoprotein. J Biol Chem. 1986;261(13):5766-5776.
14
Project title: Evaluating the off-label use of tilorone as a novel therapeutic for heart failure
Laboratory: Cardiac Hypertrophy
Primary Supervisor (s) Dr Bianca Bernardo and A/Prof Julie McMullen
Contact:
bianca.bernardo@bakeridi.edu.au
Research Focus:
Developing new therapies for the treatment of heart failure
8532 1167
Keywords: heart failure, fibrosis, tilorone, novel therapies
Synopsis: Heart failure is one of the leading clinical problems in Australia, and its significance is increasing
as the population ages. Existing therapies typically slow, rather than prevent or reverse heart failure
progression and often have undesirable side effects. Thus, innovative and efficacious therapies that can
prevent heart failure are urgently needed. Scarring (also called fibrosis) of the heart is a key clinical
correlate of declining heart function. Recently, tilorone, an FDA approved drug which is primarily
prescribed for viral infections and diarrhoea was shown to inhibit scarring in a mouse model of lung
disease. We have since generated exciting Preliminary Data that demonstrate that tilorone can regulate
the expression of a key anti-scarring pathway in heart cells called the bone morphogenetic protein
pathway, and that administration of tilorone in a mouse model of heart failure can attenuate cardiac
fibrosis.
Hypothesis: Tilorone may therefore act as a potential novel therapeutic to inhibit scarring and preserve
heart function in a setting of heart failure.
Aim: To determine the effect of tilorone on fibrosis and cardiac function in a mouse model of pathological
cardiomyopathy with established adverse cardiac remodelling, fibrosis and dysfunction.
Experimental mouse procedures (echocardiography, dissection, i.p. injections)

qPCR
Western blotting
References:
1. Lepperantra et al., 2013 Am J Respir Cell Mol Biol 48:448-55
2. Massague et al., 2005 Genes Dev 19: 2783-2810
3. Bernardo, B.C., Ooi, J.Y.Y. and McMullen, J.R. (2012) The Yin and Yang of Adaptive and Maladaptive Processes in
Heart Failure. Drug Discovery Today: Therapeutic Strategies. 9(4): e163-e172.
4. Tham, Y. K., B. C. Bernardo, J. Y. Ooi, K. L. Weeks and J. R. McMullen (2015). "Pathophysiology of cardiac
hypertrophy and heart failure: signaling pathways and novel therapeutic targets." Arch Toxicol. 89: 1401-1438, 2015
5. Zeisberg et al., 2003 Nat Med 9:964-8
15
Project title: Development of a cardiac specific miRNA drug for the treatment of heart failure
Laboratory: Cardiac Hypertrophy
Primary Supervisor (s): Dr Bianca Bernardo and A/Prof Julie McMullen
Contact:
bianca.bernardo@bakeridi.edu.au
8532 1167
Research Focus: Developing new therapies for the treatment of heart failure
Keywords: heart failure, microRNAs, tough decoy, pathological hypertrophy, adeno associated virus
Synopsis:
Heart failure is a major clinical problem which is becoming worse as the Australian population ages.
Existing therapies typically slow, rather than prevent or reverse heart failure progression and often has
side effects. Thus, new well-tolerated therapies with the ability to improve function of the failing heart are
needed. We have previously demonstrated that activation of a gene, called phosphoinositide 3-kinase
(PI3K), in settings of cardiac disease, protects the heart against cardiac dysfunction and have identified
tiny genes (called microRNAs) that are controlled by PI3K. Dr Bernardo has recently shown that silencing
these tiny genes in heart disease models with a drug was associated with reduced pathology and
improved heart function (refs 2-4). The main aim of this project is to examine the therapeutic potential of
these tiny genes using a gene therapy approach that will transport the gene directly into heart cells. This
approach has been successfully used in a number of clinical trials to treat diseases such as muscular
dystrophy. This research proposal addresses a significant problem in the cardiovascular field, that of
identifying new strategies to improve function of the failing heart.
The major outcome of this project is the development and assessment of a gene delivery system that will
directly target heart cells. This project is clinically relevant as it could lead to the development of a novel
heart-specific drug.
Aims:
1. To develop and optimise a miRNA-based therapy using a viral vector approach and microRNA tough
decoys to achieve selective knockdown of candidate microRNAs in the heart.
2. To determine whether cardiac selective inhibition of candidate microRNAs can improve cardiac function
in different mouse models of heart failure.
Experimental mouse procedures (echocardiography, dissection, i.v. injections)
qPCR
Western blotting
Cell culture / luciferase assays
Molecular cloning
Histological techniques to measure fibrosis, cell size, angiogenesis and apoptosis.
References:
1. Bernardo BC, Ooi JY, Lin RC, and McMullen JR. miRNA therapeutics: a new class of drugs with potential therapeutic applications
in the heart. Future Med Chem 7: 1751-1769, 2015.
2. Bernardo BC, Gao XM, Winbanks CE, Boey EJ, Tham YK, Kiriazis H, Gregorevic P, Obad S, Kauppinen S, Du XJ, Lin RC, and
McMullen JR. Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart
function. Proc Natl Acad Sci U S A 109: 17615-17620, 2012.
3. Bernardo BC, Nguyen SS*, Winbanks CE, Gao X-M, Boey EJH, Tham YK, Kiriazis H, Ooi JYY, Porrello ER, Igoor S, Thomas CJ,
Gregorevic P, Lin RCY, Du X-J, and McMullen JR. Therapeutic silencing of miR-652 restores heart function and attenuates adverse
remodeling in a setting of established pathological hypertrophy. FASEB J 28: 5097-5110, 2014.
4. Bernardo BC, Nguyen SS*, Gao XM, Tham YK, Ooi JYY, Patterson NL, Kiriazis H, Su Y, Thomas CJ, Lin RCY, Du X, and McMullen JR.
Inhibition of miR-154 Protects Against Cardiac Dysfunction and Fibrosis in a Mouse Model of Pressure Overload. Scientific Reports
6: 22442, 2016.
5. Xie J, Ameres SL, Friedline R, Hung JH, Zhang Y, Xie Q, Zhong L, Su Q, He R, Li M, Li H, Mu X, Zhang H, Broderick JA, Kim JK, Weng
Z, Flotte TR, Zamore PD, and Gao G. Long-term, efficient inhibition of microRNA function in mice using rAAV vectors. Nat Methods
9: 403-409, 2012.
*previous Honours student
16
Project title: The role of Gpr43 in the dietary prevention of cardiovascular disease
Laboratory: Heart Failure Research Laboratory
Primary Supervisor (s): Prof David Kaye and Dr Francine Marques
Contact:
francine.marques@bakeridi.edu.au
8532 1916
Research Focus: Cardiovascular phenotype of Gpr43 knockout mouse model, and its relevance in the
dietary prevention of high blood pressure and heart failure through the gut
Keywords
High blood pressure, heart failure, gut microbiome, next-generation sequencing
Heart failure is a common progressive disease and a major cause of death. After age, the most important
cardiovascular risk factor for heart failure is high blood pressure (i.e. hypertension) which is typically
associated with cardiac remodelling. Patients with heart failure have scarring of the heart with the
accumulation of fibroblasts and extracellular matrix, leading to stiffness and, thus, a decrease in pumping
function. While epidemiological studies show that obesity and a high fat and high sodium intake are clear
contributors to hypertension and heart failure, it is starting to emerge that other dietary components such
as fibre might also modulate cardiovascular risk factors. The mechanism, however, is not known.
Consumption of a diet high in fibre increases gut microbiota populations that, through fermentation,
generate short chain fatty acids (SCFAs), which have a protective role in experimental models of
inflammatory diseases. We have recently found that dietary manipulation with fibre or acetate can
prevent the development of high blood pressure and heart failure in a model of disease. This may happen
through the G-protein coupled receptor 43 (GPR43), a key receptor for acetate in the gut and immune
cells. The overall aim of this project is to determine the effect of Gpr43 in high blood pressure and heart
failure. This will be achieved by establishing the cardiovascular phenotype of Gpr43 knockout mice,
followed by treating these mice the different types of diet and inducing the development of
cardiovascular disease. We hypothesize that mice lacking Gpr43 will not respond to dietary fibre or
acetate intake. This project will form the basis for the development of new therapies focused on the
prevention and treatment of serious cardiovascular diseases such as heart failure.
Animal handling, including in vivo echocardiogram, cardiac catheter, metabolic cages, etc.
Molecular biology techniques, including immunohistochemistry (Massons trichrome), RNA and
DNA extraction, real-time PCR, etc.
Gut microbiome determination using next-generation sequencing
References:
1.
Marques FZ, Nelson E, Chu PY, Horlock D, Fiedler A, Ziemann M, Tan J, Kuruppu S, Rajapakse NW, El-Osta A,
Mackay CR, Kaye D. Gut microbiota, through its production of acetate, prevents the development of
hypertension and heart failure. Submitted for publication.
2.
Macia L, Tan J, Vieira AT, Leach K, Stanley D, Luong S, Maruya M, Ian McKenzie C, Hijikata A, Wong C, Binge
L, Thorburn AN, Chevalier N, Ang C, Marino E, Robert R, Offermanns S, Teixeira MM, Moore RJ, Flavell RA,
Fagarasan S, Mackay CR. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced
gut homeostasis through regulation of the inflammasome. Nat Commun; 6:6734.
3.
Thorburn AN, McKenzie CI, Shen S, Stanley D, Macia L, Mason LJ, Roberts LK, Wong CH, Shim R, Robert R,
Chevalier N, Tan JK, Mario E, Moore RJ, Wong L, McConville MJ, Tull DL, Wood LG, Murphy VE, Mattes J,
Gibson PG, Mackay CR. Evidence that asthma is a developmental origin disease influenced by maternal diet
and bacterial metabolites. Nat Commun;6:7320.
17
Project title: The role of the microRNA miR-181a in blood pressure

Laboratory: Neuropharmacology and Heart Failure Research Laboratories
Primary Supervisor (s): Prof Geoff Head and Dr Francine Marques
Contact:
geoff.head@bakeridi.edu.au
francine.marques@bakeridi.edu.au
Research Focus:
The use of a CRISPR-microRNA knockout model to determine if miR-181a regulates blood pressure
Keywords
High blood pressure, CRISPR, microRNA, animal model
High blood pressure (BP), also known as essential hypertension, is responsible for more than 50% of
cardiovascular deaths worldwide, being the principal risk factor for global burden of disease. Hypertension
is a multifactorial condition with a substantial contribution from heritable genetic factors. Unravelling the
molecular predisposition to high BP has, however, proven challenging. MicroRNAs are small non-coding
RNAs which bind to untranslated regions of many genes including those responsible for cardiovascular
disease. We found previously that the microRNA miR-181a binds to and regulates the levels of renin
mRNA in cells in culture and is inversely associated with the level of expression of renin in the kidney
(Marques et al., Hypertension 2011; Jackson et al., Hypertension 2013). This microRNA was also detected
in the circulation and was associated with BP level (Marques et al., in press). We are now developing a
knockout miR-181a mouse using the latest CRISPR technology that we expect will have higher BP. The aim
of this project will be to determine the role of miR-181a in BP determination using this newly developed
CRISPR model and telemetry. It will also involve the determination of response to stress tests in vivo, as
well as other gene targets of miR-181a beside renin that could be involved in BP regulation.
Animal models and surgeries

Blood pressure determination in vivo using telemetry
Next-generation sequencing (RNA-sequencing) and bioinformatics
Molecular biology techniques such as qPCR and cloning
References:
1.
Jackson KL, Marques FZ, Watson AM, Palma-Rigo K, Nguyen-Huu TP, Morris BJ, Charchar FJ, Davern PJ, Head
GA. A novel interaction between sympathetic overactivity and aberrant regulation of renin by miR-181a in
BPH/2J genetically hypertensive mice. Hypertension. 2013;64:775-81.
2.
Marques FZ, Campain AE, Tomaszewski M, Zukowska-Szczechowska E, Yang YH, Charchar FJ, Morris BJ. Gene
expression profiling reveals renin mRNA overexpression in human hypertensive kidneys and a role for
microRNAs. Hypertension. 2011;58:1093-8.
3. Marques FZ, Romaine S, Denniff M, Eales J, Dormer J, Garrelds I, Nelson CP, Wojnar L, Musialik K, Morris BJ,
Samani NJ, Bogdanski P, Zukowska-Szczechowska E, Danser AHJ, Charchar FJ, Tomaszewski T. Signatures of
miR-181a on blood pressure and renal transcriptome. Molecular Medicine; In press.
18
Project title: Investigating the therapeutic potential of targeting the bone morphogenetic protein
signalling pathway to combat skeletal muscle wasting
Laboratory: Muscle Research and Therapeutics
Primary Supervisor: Dr Paul Gregorevic
Contact: email: paul.gregorevic@bakeridi.edu.au
phone: 8532 - 1224
Research Focus: Developing molecular interventions to dissect mechanisms controlling skeletal muscle
attributes and generate gene therapies for conditions of muscle wasting.
Keywords: Skeletal muscle, cell signaling, growth regulation, gene therapy, wasting, cancer cachexia,
sarcopenia, muscular dystrophy, aging.
Skeletal muscle comprises approximately 40% of our body mass and performs a number of crucial bodily
functions. Loss of muscle mass and strength is a serious and unmet health risk associated with disability,
illness and premature death, having serious consequences on the vast majority of society.
The Laboratory for Muscle Research and Therapeutics Development aims to identify the molecular
mechanisms that control muscle mass and manipulate cellular signalling pathways to promote muscle
hypertrophy, metabolic function and strength in disease.
Our lab specialises in the delivery of genes to the striated muscle using recombinant viral vectors. This
cutting edge technology allows us to reveal the basic biological characteristics of skeletal muscle in vivo in
addition to providing a platform to investigate gene therapies in mouse models of skeletal muscle wasting1.
A particularly novel signalling pathway controlling skeletal muscle mass is the bone morphogenetic protein
(BMP) signaling pathway which was originally discovered for its role in stimulating bone formation. We
have recently shown that this pathway plays a vital role as a positive regulator of skeletal muscle mass 2.
Increasing BMP signaling in muscle can promote muscle growth, and counter protein breakdown 2,3. Based
on these exciting results, we are now seeking to investigate whether gene-delivery and drug based
interventions can be developed which target this pathway, as new therapeutics for muscle wasting.
The central aim of this project will be to use a number of molecular approaches to increase or reduce BMP
signalling in skeletal muscle and accompanying cell types in mouse models of disease, to determine if this
impacts on the loss of muscle mass associated with muscle wasting conditions, and impacts on lifespan.
Additional studies will examine the signaling and gene regulation associated with these effects. Research
projects are available for Honours, Masters and PhD students.
Healthy
Healthy
Muscle
Muscle
Nerve
Nerve
damage
damage
Activation
Activation
of of
muscle
musclecatabolism
catabolism
Muscle
Muscle
wasting
wasting
Viral vector
delivery
Up-regulation of
BMPs
Preservation
of muscle
mass
19
Analysing skeletal
muscle phenotypes in
vivo
Cell culture validation

of viral vector
plasmids
Molecular assays
including western
blotting and q-PCR
Designing and
administering viral
vectors in vivo
Using multiple mouse

models of skeletal
muscle wasting
Histological analysis
of mouse skeletal
muscle
Immunofluorescent
microscopy
Physiological
assessment of
skeletal muscle
function
References:
1. Gregorevic et al rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic
mice. Nat Med. 2006 Jul;12(7):787-9.
2. Winbanks et al The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J Cell Biol. 2013
Oct 28;203(2):345-57.
3. Sartori et al BMP signaling controls muscle mass. Nat Genet. 2013 Nov;45(11):1309-18.
20
Project title: Using gene therapy tools to study and treat skeletal muscle disease
Laboratory: Muscle Research and Therapeutics
Primary Supervisor(s): Dr Paul Gregorevic
Contact: paul.gregorevic@bakeridi.edu.au
phone: 8532 - 1224
Research Focus: Developing molecular interventions to understand mechanisms controlling skeletal
muscle attributes and treat conditions of muscle wasting
Keywords: Skeletal muscle, cell signaling, growth regulation, gene therapy, wasting, cancer cachexia,
sarcopenia, muscular dystrophy, aging.
Physical frailty caused by loss of skeletal muscle mass and strength is one of the main factors contributing
to disability, illness and premature death worldwide. Our goal is to elucidate how the cellular mechanisms
that regulate muscle development and adaptation become perturbed in muscle wasting, and to develop
new therapeutic approaches to reverse loss of muscle mass, strength and metabolic function.
What sets us apart is that we design and make recombinant viral vectors in-house, to regulate and
interrogate the cellular mechanisms controlling muscle adaptation in vivo with a combination of precision,
efficacy, and speed not offered by other methods. Our expertise in using gene delivery technologies to
manipulate muscle1 is unparalleled in Australia, and undertaking research with us provides a unique
opportunity to work with these cutting edge methods.
Opportunities are available to conduct studies within several of our research themes:
How does the Transforming Growth Factor- signalling network regulate muscle 2,3
Novel genes that control skeletal muscle growth and wasting 4
Using vector-based delivery of genome editing technology to study and treat disease
Novel gene therapies for neuromuscular disorders, and wasting in chronic illness
Using gene therapies to treat diabetes & diabetic complications.
Students are also welcome to discuss other projects that may fall outside of these themes, or involve
building collaborations with other teams possessing complementary expertise. Research projects are
available for Honours, Masters and PhD students.
Figure 1: Recombinant viral vectors can be used as gene delivery tools to study the regulation of muscle attributes, and potentially to treat
conditions associated with skeletal and cardiac muscle disease.
21
Analysing skeletal
muscle phenotypes in
vivo
Cell culture validation

of viral vector
plasmids
Molecular assays
including western
blotting and q-PCR
Designing and
administering viral
vectors in vivo
Using multiple mouse

models of skeletal
muscle wasting
Histological analysis
of mouse skeletal
muscle
Immunofluorescent
microscopy
Physiological
assessment of
skeletal muscle
function
References:
1. Gregorevic et al rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic
mice. Nat Med. 2006 Jul;12(7):787-9.
2. Winbanks et al The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J Cell
Biol. 2013 Oct 28;203(2):345-57.
3. Winbanks et al Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently
of myostatin. J Cell Biol. 2012 Jun 25;197(7):997-1008.
4. Chen et al Elevated expression of activins promotes muscle wasting and cachexia. FASEB J. 2014 Apr;28(4):171123.
22
Project title: Regulation of skeletal muscle mass in health and disease

Laboratory: Muscle biology and therapeutics
Primary Supervisor(s): Dr Paul Gregorevic and Dr Kevin Watt
Contact: paul.gregorevic@bakeridi.edu.au
phone: 8532-1224
Research Focus: Signalling pathways regulating skeletal muscle size, mechanisms promoting skeletal
muscle atrophy in neuromuscular disease
Keywords: skeletal muscle, hypertrophy, atrophy,
Physical frailty caused by loss of skeletal muscle mass and strength is one of the main
factors contributing to disability, illness and premature death worldwide. The goal of our laboratory is to
elucidate how the cellular mechanisms that regulate muscle development and adaptation
become perturbed in muscle wasting, and to develop new therapeutic approaches to reverse
loss of muscle mass, strength and metabolic function.
To do this we design and make recombinant viral vectors as a means to regulate and interrogate the
cellular mechanisms controlling muscle adaptation in vivo with a combination of precision, efficacy, and
speed not offered by other methods (Fig 1). Our expertise in using gene delivery technologies in skeletal
muscle 1,2 is unparalleled in Australia, and undertaking research with us is a unique opportunity to work
with cutting edge methodology.
Fig1. Schematic of rAAV production and

application in vivo
Fig2. Schematic representation of the human

Hippo signalling pathway (Harvey et al 3)
This project will interrogate the role of the Hippo signalling pathway (Fig 2) as a novel regulator of skeletal
muscle size in health and disease. This pathway is currently generating much study with numerous
examples of publications in the very highest impact journals. We have found that the Hippo signalling
pathway is also a key regulator of skeletal muscle size.4 However, the mechanisms that drive this remain
unclear. Using gene delivery technologies and a number of disease relevant models e.g. cancer cachexia
and amyotrophic lateral sclerosis we will assess the interactions between the Hippo signalling network,
and other key signalling pathways, as mechanisms governing skeletal muscle size in health and disease.
Research projects are available for Honours, Masters and PhD students.
23
Range of molecular biology methods (Western blotting, q-RT-PCR, Histology, Cell culture, In vivo
manipulation of gene expression)
Design, manufacture and administration in vitro and in vivo of recombinant viral vectors.
Animal models of disease. Small animal handling, and surgical procedures.
References:
1. Gregorevic P. et al rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic
mice. Nat Med. 2006 12(7):787-9.
2. Winbanks C.E. et al The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J Cell
Biol. 2013 203(2):345-57.
3. Harvey K.F, Zhang X., Thomas D.M. The Hippo pathway and cancer. Nat Rev Cancer 2013 Apr;13(4):246-57
4. Watt K.I. et al The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size. Nat Comm 2015
6:6048.
24
Project title: Development of brown adipose tissue for treatment of obesity

Laboratory: Metabolic & Vascular Physiology
Primary Supervisor (s) Andrew Carey & Bronwyn Kingwell
Contact: andrew.carey@bakeridi.edu.au
bronwyn.kingwell@bakeridi.edu.au
Research Focus: Study of brown adipose (fat) in humans as a potential treatment for obesity
Keywords Obesity, diabetes, fat, brown fat, brown adipose tissue, energy expenditure
Project description: 200-250 words (or less), synopsis of the project, highlighting the main features of the
project (including the potential research question, aim, rationale). Images or graphics maybe added.
Fundamentally, obesity results from an imbalance between energy intake and expenditure. Current
preventative and therapeutic approaches have been either unsustainable or result in significant negative
side effects. Brown adipose tissue (BAT) is unique with respect to its sole function of burning potentially
great quantities of energy, therefore increasing BAT content and activity is currently considered one of the
most promising strategies to increase energy expenditure to combat obesity. BAT function in small animals
is well described, however in humans knowledge is limited due to only recently being conclusively identified
in adults and the identification of novel techniques to measure its activity.
Our ongoing studies therefore provide opportunities to explore the possibility of combating obesity related
disease while gaining broad research experience and skills ranging from clinical research to numerous wet
lab techniques.

Numerous aspects of human clinical research, including
Volunteer recruitment
Tissue collection
Body composition analysis
Measurement of whole body energy expenditure
Examination of nuclear medicine scans for BAT activity
Basic Science/wet laboratory analytical techniques
Opportunity to discuss your work regularly to both lay people and those involved in research
References:
1.
2.
Carey and Kingwell (2013). Brown adipose tissue in humans: Therapeutic potential to combat obesity.
Pharmacology and Therapeutics. 140: 26-33
Carey et al. (2015) Chronic ephedrine administration decreases brown adipose tissue activity in randomised
controlled human trial: implications for obesity. Diabetologia. 58:10451054
25
Project title: Modifiable lifestyle behaviors and health outcomes in the Australian population
Laboratory: Metabolic and Vascular Physiology
Primary Supervisor (s): Ms. Erin Hoare, Prof. Bronwyn Kingwell, Prof. Garry Jennings
Contact:
Erin.Hoare@bakeridi.edu.au
Research Focus:
Population health; epidemiology; health behavior; psychology
8532 1166
Keywords
Diet/nutrition; physical activity; sedentary behavior; non-communicable disease; mental health
Lifestyle driven disease represents a global public health crisis. Affordability and availability of energy
dense foods has given way to unhealthy dietary patterns, and technological advances have led to physical
inactivity, and increased sedentary lifestyles. Such behaviours contribute to the development and
maintenance of non-communicable diseases (NCDs), being chronic, non-infectious conditions that develop
over time. Collectively, NCDs including heart disease, stroke, cancer, diabetes and chronic lung disease,
are responsible for almost 70% deaths worldwide (1). In Australia during 2008, NCDs accounted for
approximately 90% of all mortality (2). Modifiable lifestyle behaviours are key determinants of NCDs, and
such diseases are therefore, theoretically, preventable (1). Population-level evidence is needed to
understand and explore the complexity of lifestyle behaviours and associated NCD and other health
outcomes.
This research program examines existing population-level data sets, comprising detailed nutrition, physical
activity and sedentary behavioural components, and non-communicable disease outcomes including
cardiovascular disease, diabetes, overweight/obesity, and mental illness. Qualitative data reporting
attitudes towards lifestyle behaviours and disease outcomes are also available. The potential research
projects* for students projects may include;
Sugar sweetened beverage consumption and cardiovascular health; the role and impact of
physical activity
What are the socio-demographic correlates of physical inactivity and sedentary behaviour among
the Australian adult population?
The relationship between lifestyle behavioural risk factors and psychological distress among
Australian adults aged 18-24
A qualitative evaluation of Australian adults attitudes and behaviours toward healthy eating and
physical activity
*Potential research projects listed here are not exhaustive and there is opportunity for
prospective students to develop own research focus within the above context.

Working with large, population-level data sets
Quantitative/qualitative methodology
Writing for academic and research publication
References:
1.
2.
3.
World Health Organization (2015). Fact Sheet, Noncommunicable disease, viewed 18 July 18, 2016,
<http://www.who.int/mediacentre/factsheets/fs355/en/>
Moodie, A. R., Tolhurst, P., & Martin, J. E. (2016). Australias health: being accountable for prevention. Med J Aust,
204(6), 223-225.
Australian Indigenous HealthInfoNet. Overview of Australian Indigenous Health Status (2013), viewed 18 July 2016,
<http://www.healthinfonet.ecu.edu.au/health-facts/overviews>
26
Project title:
Investigating the interacting effects of exercise and breaking up sitting on appetite regulation in
overweight/obese adults
Laboratory: Physical Activity
Primary Supervisor (s): Dr Robyn Larsen , Dr Megan Grace
Contact: Robyn.Larsen@bakeridi.edu.au
Research Focus:
Exercise physiology and appetite regulation
Keywords
Exercise, sedentary behaviour and appetite regulation
Appetite regulation may have implications for the health of an individual due to its role in weight
management. Appetite regulation is the result of a complex interplay between individual eating
behaviour, perceptions of hunger and satiety as well as the underlying hormones related to energy
balance and appetite.
Sedentary behaviour can induce weight gain due to low energy expenditure and energy surplus. Exercise
has beneficial effects on weight and appetite hormones, however this does not always translate to
changes in perception of hunger and satiety [1]. Individual differences in eating behavior are important in
understanding the effect of exercise on appetite regulation, where some individuals are energy
compensators and others are energy non compensators in response to exercise, which affects the
resulting energy balance [2]. Another interesting area of research is that of breaking up prolonged
sitting, which may help to induce energy deficit, but without changing appetite hormones [3].
This honours project will take advantage of a clinical trial that is currently underway in the Physical Activity
Laboratory at Baker IDI, and will investigate appetite in response to exercise and sedentary behaviour. The
aim of this honours project is to compare appetite regulation changes following three 8-hour
experimental conditions, occurring 6 days apart:
Uninterrupted sitting
Exercise (30-minutes) + uninterrupted sitting
Exercise (30-minutes) + interrupted sitting (3-minute walk/every 30-minutes)
Appetite regulation will be assessed by measuring individual eating behaviour, perceptions of hunger and
satiety and key appetite hormones. The student will work closely with the research team, gaining
experience in laboratory techniques, as well as clinical trial design and conduct.
Laboratory experiments (radioimmunoassay)

Clinical trial conduct and design
Statistical analysis
References:
[1]
[2]
[3]
C. Martins, D. Stensvold, G. Finlayson, J. Holst, U. Wisloff, B. Kulseng, L. Morgan, and N. a. King, Effect of moderate- and high-intensity
acute exercise on appetite in obese individuals, no. April 2014. 2014.
N. a. King, K. Horner, a. P. Hills, N. M. Byrne, R. E. Wood, E. Bryant, P. Caudwell, G. Finlayson, C. Gibbons, M. Hopkins, C. Martins, and J.
E. Blundell, Exercise, appetite and weight management: understanding the compensatory responses in eating behaviour and how they
contribute to variability in exercise-induced weight loss, Br. J. Sports Med., vol. 46, pp. 315322, 2012.
D. P. Bailey, D. R. Broom, B. C. R. Chrismas, L. Taylor, E. Flynn, and J. Hough, Breaking up prolonged sitting time with walking does not
affect appetite or gut hormone concentrations but does induce an energy deficit and suppresses postprandial glycaemia in sedentary
adults, Appl. Physiol. Nutr. Metab., pp. 131, Dec. 2015.
27
Project title:
The effect of exercise and breaking up sitting on postprandial insulin-like growth factor binding protein
responses in overweight/obese adults
Primary Supervisor (s): Dr Robyn Larsen and Dr Megan Grace
Contact:
Robyn.Larsen@bakeridi.edu.au
8532-1859
Research Focus:
Understanding the impact of reducing sitting time on biological mechanisms relating cancer risk
Keywords
Sedentary behaviour and Cancer
There is increasing recognition that cancer growth may be promoted by high plasma insulin levels.
Sedentary behaviour, diabetes, obesity and inactivity are known risk factors for cancer, and they all share
an association with elevated glucose and insulin levels.1 This association may be mediated, in part, by
changes to the insulin-like growth factor (IGF) system.2 Food intake directly influences the IGF system by
acutely altering levels of IGF-binding proteins (IGFBPs), thereby reducing the amount of free, biologically
active IGF-1 that is available to tissues. Two such binding proteins, IGFBP-1 and IGBFP-3, have been shown
to be sensitive to changes in glucose and insulin levels.3 However, little is known about the impact of
sedentary behaviours (prolonged sitting) on the IGF-1 system.
Our laboratory has previously shown that uninterrupted sitting is associated with elevated postprandial
glucose and insulin responses compared to sitting that is broken up with short bouts of physical activity.
We hypothesize that the IGF axis may be responsive to the experimental manipulation of sitting time,
providing a plausible biologic mechanism for increasing cancer risk. The aim of this study is to compare
IGF-1 system changes following three (8-hour) experimental conditions:
Uninterrupted sitting
Exercise (30-minutes) + uninterrupted sitting
Exercise (30-minutes) + interrupted sitting (3-minute walk/every 30-minutes)
This honours project will take advantage of an existing clinical trial that is currently underway in the
Physical Activity laboratory. The student will work closely with the research team, gaining experience in
laboratory techniques, as well as clinical trial design and conduct.
Laboratory experiments (radioimmunoassay)

Clinical trial conduct and design
References:
1. Katzmarzyk, Peter T., et al. "Sitting time and mortality from all causes, cardiovascular disease, and
cancer." Med Sci Sports Exerc 41.5 (2009): 998-1005.
2. Giovannucci, Edward. "Insulin and colon cancer." Cancer Causes & Control 6.2 (1995): 164-179.
3. Brand-Miller, Jennie C., et al. "The glycemic index of foods influences postprandial insulin-like
growth factorbinding protein responses in lean young subjects." The American journal of clinical
nutrition 82.2 (2005): 350-354.
28
Project title:
The effect of breaking up sitting on subsequent 24-hour ambulatory blood pressure in
overweight/obese adults
Primary Supervisor (s): Dr Robyn Larsen and Dr Rachel Climie
Contact:
Robyn.Larsen@bakeridi.edu.au
8532-1859
Research Focus:
Understanding the impact of reducing sitting time on risk factors for cardiovascular disease
Keywords
Sedentary behaviour, blood pressure
Regular physical activity is a well-accepted approach for the primary prevention of hypertension and is
recommended as an adjunct to pharmacotherapy for the secondary prevention of cardiovascular disease.
However, emerging evidence suggests that another set of behaviours, involving prolonged sitting, can
adversely affect blood pressure (BP) even when meeting physical activity guidelines. We have previously
shown in our experimental studies that breaking up sitting acutely lowers systolic BP and diastolic BP in
overweight and obese sedentary adults.1,2 This project will build on a current experimental study and aims
to determine whether or not the beneficial BP lowering effects demonstrated in the laboratory extend
beyond the experimental period.
The project will involve recruitment of 10 overweight/obese but otherwise healthy participants, who will
complete two conditions in a randomised order at the Baker IDI clinical laboratory facilities:
(i)
Prolonged sitting condition. Participants will be asked to sit uninterrupted for 5 hours,
following a standardised breakfast meal
Interrupted sitting condition. Participants will interrupt their 5 hour sitting period with 3
minutes of light-intensity body-weight resistance activities every 30 minutes
(ii)
Twenty-four hour ambulatory BP monitors (ABPM) will be fitted at the end of each experimental condition
to monitor BP in the post-experimental period.
This project will be undertaken as part of a larger trial, which is expected to result in multiple research
outcomes. The student will be encouraged to take part in participant recruitment, co-ordination of testing
procedures, data collection, data analysis, and potentially manuscript preparation.
Good clinical practice

Clinical research and participant recruitment
References:
1. Larsen, R. N., et al. "Breaking up prolonged sitting reduces resting blood pressure in
overweight/obese adults." Nutrition, Metabolism and Cardiovascular Diseases 24.9 (2014): 976982.
2. Dempsey, P., et al Interrupting Prolonged Sitting with Brief Bouts of Light Walking or Simple
Resistance Activities Reduces Resting Blood Pressure and Plasma Norepinephrine in Type 2
Diabetes Journal of Hypertension, In press
29
Project title:
Effects of Prolonged Sitting on Retinal Microvascular Function in Overweight/Obese Adults
Laboratory: Physical Activity Laboratory
Primary Supervisor (s): Megan Grace, Rachel Climie
Contact:
Megan Grace
Megan.Grace@bakeridi.edu.au
8532 1855
Research Focus:
Understanding the effects of prolonged sitting on the retinal microvasculature, and how this may be
associated with risk of retinal damage
Keywords
Sedentary behaviour, microvascular function, retinopathy
In the last few decades, advances in transportation, communication, entertainment technologies and
workplace settings have led to a dramatic reduction in the amount of physical activity performed
throughout a typical day, and an increase in time spent sitting. Such sedentary behaviours have been
linked to increased risk of type 2 diabetes and its complications. Two cross-sectional epidemiological
studies show an association between high television viewing time and impaired retinal microcirculation1,2.
We have previously shown in our experimental studies that breaking up sitting acutely lowers post meal
glucose and insulin levels and resting blood pressure in overweight and obese sedentary adults3,4.
However, the effects of prolonged sitting on retinal microvascular function have not been directly
assessed in an experimental trial.
The aim of this project is to investigate the effects of prolonged sitting (5 hours) on retinal microvascular
function. The project will involve recruitment of 10 overweight/obese but otherwise healthy participants,
who will complete two conditions in a randomised order at the Baker IDI clinical laboratory facilities:
(i)
(ii)
Prolonged sitting condition. Participants will be asked to sit uninterrupted for 5 hours,
following a standardised breakfast meal
Interrupted sitting condition. Participants will interrupt their 5 hour sitting period with 3
minutes of light-intensity body-weight resistance activities every 30 minutes
Retinal scans will be taken at baseline and 5-hours.

This project will be undertaken as part of a larger trial, which is expected to result in multiple research
outcomes. The student will be encouraged to take part in participant recruitment, co-ordination of testing
procedures, data collection, data analysis, and potentially manuscript preparation.
Clinical research and participant recruitment
Good clinical practice training
Retinal imaging
References:
1. Anuradha et al. Physical activity, television viewing time, and retinal vascular caliber. Med Sci Sports Exerc, 2011.
43(2): 280-286
2. Anuradha et al. Physical activity, television viewing time, and retinal microvascular caliber: the multi-ethnic study
of atherosclerosis. Am J Epidemiol, 2011. 173(5): 518-525
3. Dunstan et al. Breaking up prolonged sitting reduced postprandial glucose and insulin responses. Diabetes Care,
2012. 35: 976-983.
4. Larsen et al. Breaking up prolonged sitting reduces resting blood pressure in overweight/obese adults. Nutrition,
Metabolism and Cardiovascular Diseases, 2014. 24(9): 976-982.
30
Project title:
Role of allopregnanolone in treating neurogenic hypertension in mice
Laboratory: Neuropharmacology Laboratory
Primary Supervisor (s): Dr Kristy Jackson, Dr Pamela Davern and Prof Geoff Head
Contact:
kristy.jackson@bakeridi.edu.au
8532 1333
pamela.davern@bakeridi.edu.au
8532 1330
8532 1332
Research Focus: : The influence of the central nervous system on long-term blood pressure levels and the
relationship between blood pressure and stress pathways in the brain is a major focus of studies in the
Neuropharmacology Laboratory. Research in neuropharmacology centres on cardiovascular neuroscience
and fills a niche between the clinic and basic research.
Keywords
Hypertension, Brain, GABA receptors, Allopregnanolone, Stress, Sympathetic nervous system
Project description: We have shown that genetically
hypertensive mice (BPH, Blood Pressure High) have
hypertension due to an overactive sympathetic nervous system
compared with control mice (BPN, Blood Pressure Normal).
The mechanism is related to GABA receptor dysfunction and
allopregnanolone (AlloP) is an endogenous neurosteroid and
allosteric modulator of GABA receptors. We hypothesise that
reductions in brain AlloP cause reduced inhibitory GABAergic
activity in the amygdala and hypothalamus leading to elevated
sympathetic nerve activity and neurogenic hypertension. Our
aim is to investigate the effectiveness and mechanism of action of AlloP treatment for neurogenic
hypertension. In this study AlloP or vehicle will be administered via minipump for 2 weeks to male and
female BPN and BPH mice. Mice will undergo a range of stress and anxiety tests (eg restraint, cage swap,
and elevated maze) both before and after treatment and blood pressure and heart rate will be recorded
via radiotelemetry probes. At the end of the experimental period brains will be examined by
immunohistochemistry and real time quantitative PCR to assess the influence of GABA receptors.
Animal handling and surgery
Direct measurement of blood pressure in conscious freely moving mice
Stress tests to measure reactivity to aversive and non-aversive stress
Immunohistochemical and qPCR analysis of brain regions
References:
1. Jackson KJ et al., Major contribution of the medial amygdala to hypertension in BPH/2J genetically
hypertensive mice. Hypertension 2014, 63(4): 811-818.
2. Davern PJ et al., GABAA receptor dysfunction contributes to high BP and exaggerated response to
stress in Schlager genetically hypertensive mice. Journal of Hypertension 2014, 32(2): 352-362.
3. Jackson KJ et al., A novel interaction between sympathetic overactivity and aberrant rgulation of
renein by mir-181a in BPH/2J genetically hypertensive mice. Hypertension 2013, 62(4): 775-781.
4. Davern PJ et al., Role of the sympathetic nervous system in Schlager genetically hypertensive mice.
Hypertension 2009, 54(4): 852-859.
31
Project title:
Central effects of chronic stress and mild activation of the renin angiotensin system on blood pressure
Primary Supervisor (s): Dr Pamela Davern, Dr Kristy Jackson and Prof Geoff Head
Contact:
8532 1330
kristy.jackson@bakeridi.edu.au
8532 1333
85321332
Research Focus: The influence of the central nervous system on long-term blood pressure levels and the
relationship between blood pressure and stress pathways in the brain is a major focus of studies in the
and fills a niche between the clinic and basic research. Work is carried out to understand the mechanisms
that trigger cardiovascular diseases through environmental factors. Stress is a main area of investigation
and research is also being conducted on its effects on the central nervous system and in response to mild
activation of the renin angiotensin system.
Keywords
Hypertension, Chronic stress, Renin angiotensin system, Brain, Sympathetic nervous system
MAP (mmHg)
The effects of acute stress have been well documented in the literature but
40
***
the mechanisms by which chronic stress or repeated daily exposure to acute
stress contributes to sustained elevations in blood pressure is not well
20
understood. The critical factor leading to a marked amplification of
cardiovascular responses does not appear to arise from chronic stress per se
0
NS
CS
but requires a combination with either (i) a follow up acute novel stress
experience or (ii) low subpressor increases in circulating angiotensin II. Our Chronic stress exposure
laboratory has data that indicates elevated neuronal nitric oxide synthase increases BP to an acute
and NADPH oxidase in neurons that are activated in response to novel stress. novel stress in mice
This observation is also associated with elevated blood pressure and
identified in brain regions such as the amygdala and hypothalamus that are known to regulate
sympathetic output to influence the kidney. In this study we will repeatedly expose mice administered a
mild subcutaneous dose of angiotensin II via a minipump or vehicle to a stress on a daily basis over two
weeks and record their blood pressure, heart rate and activity continuously via radiotelemetry devices.
Following a final novel acute stress cardiovascular parameters, neuronal activation and associated
neurochemical signatures will be immunohistochemically examined.
Direct measurement of blood pressure in conscious freely moving mice
Stress tests to measure reactivity to aversive and non-aversive stress
Immunohistochemical analysis of brain regions
References:
1. Davern PJ et al., GABAA receptor dysfunction contributes to high BP and exaggerated response to
stress in Schlager genetically hypertensive mice. Journal of Hypertension 2014, 32(2): 352-362.
2. Davern and Head, Role of the medial amygdala in mediating responses to aversive stimuli leading to
hypertension. Clin Exp Pharmacol Physiol 2011, 38: 136-143.
3. Davern PJ et al., Cardiovascular reactivity and neuronal activation to stress in schlager genetically
hypertensive mice. Hypertension 2010, 170: 551-558.
4. Davern PJ et al., Cardiovascular responses to aversive and non-aversive stressors in schlager
genetically hypertensive mice. American Journal of Hypertension 2010, 23: 838-844.
32
Project title:
Role of leptin and melanocortin in neuronal plasticity as a cause of obesity-related hypertension
Primary Supervisor (s): Dr Joon Lim, Dr Pamela Davern and Prof Geoff Head
Contact:
joon.lim@bakeridi.edu.au
8532 1333
8532 1330
8532 1332
Research Focus: The influence of the central nervous system (CNS) on long-term blood pressure (BP)
levels and the relationship between BP and stress pathways in the brain is a major focus of studies in the
and fills a niche between the clinic and basic research. Work is carried out to understand the mechanisms
that trigger cardiovascular diseases through environmental factors. Obesity induced by a high fat diet is a
main area of investigation and research is also being conducted into its effects in the CNS.
Keywords
Hypertension, Obesity, Brain, Leptin, Melanocortin, Sympathetic nervous system
A high fat diet induces hypertension and we have established in a rabbit model of obesity-related
hypertension that the elevated sympathetic nerve activity to the kidney can be abolished by inhibiting the
leptin or melanocortin receptors in the hypothalamus. The key to understanding obesity-related
hypertension is to determine what changes occur in these central signaling pathways. We suggest that the
likely mechanism is melanocortin signaling amplification mediated by a recently described neuronal
plasticity process following activation of brain derived neurotrophic factor (BDNF) and other kinases such
as MEK and ERK. Our hypothesis is that the mechanism underlying obesity-related hypertension is
increased sympathetic nerve activity to the kidney driven by
amplified neuronal plasticity of melanocortin sympathoexcitatory pathways in the hypothalamus (see figure). In this
study rabbits will be placed on a normal diet or a high fat diet for
3 weeks and immunohistochemistry will be used to (i) assess key
components of the leptin-melanocortin signaling pathways, and
(ii) identify morphological changes in dendritic length and density
as a measure of neuronal plasticity.
Direct measurement of blood pressure in conscious rabbits
Immunohistochemical analysis of brain regions
Real-time quantitative PCR
References:
1. Lim K et al., The origin of aberrant BP and sympathetic regulation in diet induced obesity.
Hypertension 2016, 68: in press.
2. Head GA et al., CNS dysfunction in obesity induced hypertension. Curr Hypertens Rep 16(9): 466-474.
3. Armitage JA et al., Rapid onset of renal sympathetic nerve activation in rabbits fed a high-fat diet.
Hypertension 2012, 60: 163-171.
4. Lim K et al., Obesity related hypertension and the role of insulin and leptin in high fat fed rabbits.
Hypertension 2013, 61(3): 628-634.
33
Project title: New Cellular Cholesterol Transporter

Laboratory: Lipoproteins and Atherosclerosis
Primary Supervisor (s): Prof. Dmitri Sviridov, Dr. Ying Fu
Contact:
Dmitri.Sviridov@bakeridi.edu.au
8532 1363
Research Focus: Treatment for atherosclerosis and diabetes
Keywords: Atherosclerosis, lipids, diabetes, heart disease, vascular biology
Atherosclerosis is the cause of majority of cardiovascular diseases, a major cause of death in Western
societies. Atherosclerosis is essentially accumulation of excessive cholesterol in the walls of arteries with
the formation of atherosclerotic plaque blocking the blood flow and causing thrombosis. Accumulation of
cholesterol may be caused by excessive delivery of cholesterol from blood or by damaged pathways
responsible for eliminating excess of intracellular cholesterol. Disturbances in intracellular cholesterol
metabolism are the primary cause of impairment of cholesterol release and are on the full front of rapidly
emerging anti-atherosclerotic therapies. Cholesterol homeostasis also plays a key role in diabetes:
accumulation of cholesterol in cells severely disrupts insulin secretion.
A key element of intracellular cholesterol metabolism is a group of proteins moving cholesterol around
the cell called ABC transporters. ABC transporters regulate release of cholesterol from cells to plasma and
maintain correct intracellular cholesterol content. Surprisingly, very little is known about how these
transporters work.
We have recently discovered that one of the transporters, ABCA12, which was known to play an important
role in skin, also plays an important role in macrophages, cell central for development of atherosclerosis
and inflammation and in cells. It appears that ABCA12 is responsible for regulating the regulator
modulating a major pathway responsible for coordinate action of other ABC transporters. The same
pathway is also involved in regulation of inflammation. The study is a combination of sophisticated in vitro
study aimed at discovering the molecular and cellular mechanisms of how ABCA12 regulates this pathway,
and in vivo study aimed at testing the effects of ABCA12 deficiency on development of atherosclerosis and
diabetes in mouse model of these diseases. The project is conducted in collaboration with Monash
University.
Cell biology
Animal models
References:
1. Fu Y, Mukhamedova N, Ip S, et al. ABCA12 Regulates ABCA1-Dependent Cholesterol Efflux from
Macrophages and the Development of Atherosclerosis. Cell Metabolism. 2013;18:225-38.
2. Smyth I, Hacking DF, Hilton AA, et al. A mouse model of harlequin ichthyosis delineates a key role for
abca12 in lipid homeostasis. PLoS Genet. 2008;4:e1000192.
34
Project title: Apolipoprotein A-1 Binding Protein as a potential treatment for atherosclerosis
Primary Supervisor: Prof. Dmitri Sviridov
Contact:
dmitri.sviridov@bakeridi.edu.au
8532 1363
Research Focus:
Treatment of Atherosclerosis
Keywords
Atherosclerosis, cholesterol, novel therapy, apoA-1, apoA-1 binding protein
Maintaining cholesterol homeostasis in cells is critical as studies have shown that imbalanced cholesterol
metabolism could lead to cardiovascular complications such as atherosclerosis. Cholesterol efflux is a tightly
regulated cellular process of removing excess cholesterol that involves cell surface transporters and their
corresponding acceptors (apolipoprotein A-1 (apoA-1) and HDL i.e. good cholesterol). Cholesterol is then
transported to the liver where it is metabolized and excreted in a process collectively known as the Reverse
Cholesterol Transport (RCT) pathway. Many studies have shown an inverse association between HDLs
cholesterol efflux capacity and the development of atherosclerotic cardiovascular diseases. As such, an
ability to increase the rate of cholesterol efflux from cells would be desirable. Recent studies have revealed
that cholesterol efflux to apoA-1 and HDL was increased in the presence of ApoA-1 Binding Protein (A1BP).
However, its mechanism in facilitating this increase remains unclear. We aim to elucidate the mechanism
and function of how A1BP enhances cholesterol efflux and also determine if A1BP possesses an ability to
improve HDLs other athero-protective abilities (e.g. anti-inflammatory) in hopes to discover its therapeutic
properties in the mitigation of atherosclerosis development.
Reverse Cholesterol Transport Pathway

in vitro studies - cell culture
Cholesterol efflux - radiolabeled assays
Protein biochemistry - western blotting
Gene expression - qRT-PCR
References:
1. Rohatgi , A., et al. (2014). "HDL Cholesterol Efflux Capacity and Incident Cardiovascular Events." New England Journal
of Medicine 371(25): 2383-2393.
2. Fang, L., et al. (2013). "Control of angiogenesis by AIBP-mediated cholesterol efflux." Nature 498(7452): 118-122.
3. Zhang, M., et al. (2016). "Apolipoprotein A-1 binding protein promotes macrophage cholesterol efflux by facilitating
apolipoprotein A-1 binding to ABCA1 and preventing ABCA1 degradation." Atherosclerosis 248: 149-159.
35
Project title: Novel Pathogenic Mechanisms of HIV-Associated Neurocognitive Disorder

Primary Supervisor (s): Prof. Dmitri Sviridov, Dr. Michael Ditiatkovski
Contact:
Dmitri.Sviridov@bakeridi.edu.au
8532 1363
Research Focus: To examine the role changes to cholesterol metabolism as an underlying mechanism for
initiation and progression of HIV-Associated Neurocognitive Disorder
Keywords: HIV, HIV-associated neurocognitive disorder, Lipid rafts, Cholesterol metabolism
HIV-associated neurocognitive disorder (HAND) is a frequent and debilitating complication of HIV disease;
its manifestations have considerable similarities, but also distinct differences, to more common forms of
dementia, such as Alzheimers disease. While the effective treatment of HIV infection has reduced the rate
of progression and severity of HAND symptoms, the incidence of HAND (50% of HIV patients) has not been
affected by the treatment.
One common element of most neurodegenerative diseases is an impairment of cholesterol metabolism.
We have previously found that accumulation of cholesterol and the associated increase in lipid rafts
contribute to the formation of protein aggregates (prions). We have also demonstrated that HIV protein
Nef, acting via ABCA1 pathway, stimulates cholesterol aggregation and increased abundance of lipid rafts.
Recent publications showed that HIV-infected cells are not only capable of secreting Nef, but can also
secrete exosomes that contain Nef and/or Nef mRNA capable of being translated in other cells. We
propose that changes to lipid metabolism by Nef drives the initiation and development of HAND. In this
project, we aim to test our hypothesis that the HIV protein Nef or exosomes containing Nef, secreted by
the HIV-infected cells into systemic and brain circulation, causes modifications of lipid rafts in bystander
cells, including neurons.
Cell Culture
Radioisotopic assays
Immunoflourescence/confocal microscopy
Flow cytometry
Western blots and other immunoassays
Exosome purification/characterisation
References:
1. Gannon, P., M. Z. Khan and D. L. Kolson (2011). "Current understanding of HIV-associated neurocognitive disorders
pathogenesis." Curr Opin Neurol 24(3): 275-283.
2. Cui, H. L., A. Grant, N. Mukhamedova, T. Pushkarsky, L. Jennelle, L. Dubrovsky, K. Gaus, M. L. Fitzgerald, D. Sviridov
and M. Bukrinsky (2012). "HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with
ABCA1-dependent cholesterol efflux." J. Lipid Res. 53(4): 696-708.
3. Cui, H. L., B. Guo, B. Scicluna, B. M. Coleman, V. A. Lawson, L. Ellett, P. J. Meikle, M. Bukrinsky, N. Mukhamedova, D.
Sviridov and A. F. Hill (2014). "Prion Infection Impairs Cholesterol Metabolism in Neuronal Cells." J. Biol. Chem. 289(2):
789-802.
4. Khan, M. B., M. J. Lang, M. B. Huang, A. Raymond, V. C. Bond, B. Shiramizu and M. D. Powell (2016). "Nef
exosomes isolated from the plasma of individuals with HIV-associated dementia (HAD) can induce Abeta1-42
secretion in SH-SY5Y neural cells." J Neurovirol 22(2): 179-190.
36
Project title: Cholesterol metabolism and complications of HIV disease

Primary Supervisor (s): Prof. Dmitri Sviridov, Dr. Nigora Mukhamedova
Contact:
Dmitri.Sviridov @bakeridi.edu.au
8532 1363
Research Focus: Pathogenesis of metabolic complications of HIV disease
Keywords: HIV, atherosclerosis, lipids, diabetes, heart disease, vascular biology
Current treatment for HIV infection has dramatically reduced mortality, however, co-morbidities that are
not directly related to immunodeficiency are now increasingly recognized as a consequence of HIV
infection. One such co-morbidity is an increased risk of cardiovascular and metabolic disease. The current
view is that HIV infection and/or its treatment are associated with elevated risk of development of
atherosclerosis and consequently with increased prevalence of acute and chronic cardiovascular events.
HIV also causes disturbances of lipoprotein metabolism, metabolic syndrome, lipodystrophy, dementia.
We currently investigate how HIV is causing co-morbidities in the organs not infected with the virus. Our
hypothesis is that HIV-infected cells release viral proteins and MiRs in the bloodstream that affect
uninfected cells causing pathology in these cells without infection. Our study is focused on establishing
how factors released by HIV-infected cells affect uninfected cells. Our hypothesis, supported by large
volume of data, is that an affected pathway is the pathway related to cholesterol metabolism.
The project is a combination of in vitro work in cell culture and animal studies.
It is on the crossroads of virology and cardiology and gives an opportunity to learn a wide range of
techniques, from cell biology to biochemistry as well as clinical studies. The project is conducted in
collaboration with a number of Australian and overseas laboratories and gives the participants an
exposure to research in various disciplines.
Cell biology
Molecular biology
Animal models
References:
1. Cui HL, Ditiatkovski M, Kesani R, et al. HIV protein Nef causes dyslipidemia and formation of foam
cells in mouse models of atherosclerosis. FASEB J. 2014; 28: 2828-2839.
2. Cui HL, Grant A, Mukhamedova N, et al. HIV-1 Nef mobilizes lipid rafts in macrophages through a
pathway that competes with ABCA1-dependent cholesterol efflux. J Lipid Res. 2012;53:696-708.
3. Mujawar, Z., Rose, H., Morrow, M. P.,et al. Human Immunodeficiency Virus Impairs Reverse
Cholesterol Transport from Macrophages, PLoS Biology 2006; 4, e365.
37
Project title: Plasmalogen modulation as a treatment for atherosclerosis

Laboratory: Metabolomics
Primary Supervisor (s): A/Prof Peter Meikle
Contact:
peter.meikle@bakeridi.edu.au
8532 1770
Research Focus: Metabolomics is the systematic study of the unique metabolite (small-molecule)
fingerprints of biological systems. The Metabolomics Laboratory uses state of the art tandem mass
spectrometry to obtain metabolic/lipid profiles from cell and animal models in addition to clinically
relevant human samples to develop new approaches to early diagnosis, risk assessment and therapeutic
monitoring of diabetes and cardiovascular disease [1]. This approach is also combined with cell biology
and animal studies to investigate lipid metabolism and pathogenesis in atherosclerosis and other disease
states. The Metabolomics Laboratory has a number of project areas that are suitable for Honours,
Masters and PhD programs.
Keywords: Heart disease; atherosclerosis, therapy, lipids, plasmalogens,
Project description: Atherosclerosis (AS) is the single most common cause of cardiovascular disease and is
the major contributor to the development of angina, heart attacks, congestive heart failure, peripheral
vascular disease and stroke. We have performed detailed lipidomic analysis of plasma and lipoproteins
from healthy individuals as well as stable and unstable
C57/BL6
ApoE KO
coronary artery disease (CAD) patients. We identified
associations of phosphatidylcholine plasmalogens with stable
0% BA 2% BA
0% BA 2% BA
CAD (relative to healthy control individuals) and of
Arch
phosphatidylethanolamine plasmalogens with unstable CAD
(relative to stable CAD) (1). We have supplemented the diet
of ApoE mice with batyl alcohol (a plasmalogen precursor);
this resulted in a four-fold increase in plasma levels of
plasmalogens and a significant attenuation of plaque
formation (average 70%) across all regions of the aorta (2).
Thoracic
supplementation
prevented
Figure.
Plasmalogen
plasmalogen progression in ApoE deficient mice.
Representative en face aortic images, showing arch, thoracic,
and abdominal sections from C57/BL6 and ApoE KO mice
with and without 2% BA treatment for 12 weeks. Areas
stained in red are atherosclerotic plaques.
Abdominal
We hypothesize that: Upregulation of plasmalogens

prevents plaque formation by multiple mechanisms,
including: 1) alteration of lipoprotein structure and function;
2) reduction in oxidative stress in tissue beds; and 3) suppression of the inflammatory response leading
to a reduction of the monocyte-endothelium interaction.
In this project we will combine our lipidomics and lipoprotein expertise with our established cell and
mouse models of oxidative stress, atherosclerosis and unstable plaque to define the mechanism(s) of
plasmalogen attenuation of plaque and to define the effect on plaque regression and stability.
38
The specific aims are to:

1) Optimise the plasmalogen modulation protocol
2) Characterise the mechanisms by which plasmalogens attenuate plaque progression
3) Assess the capacity of plasmalogens to regress plaque.
4) Determine the ability of plasmalogens to prevent plaque instability
This project will provide a mechanistic understanding of the effect and extent of plasmalogen modulation
on atherosclerosis and identify suitable endpoints for clinical trials.
Importantly, up-regulation of plasmalogen levels in animals and humans can be achieved using oral
administration of the natural compounds (alkylglycerols) and so progression into clinical trials will be rapid
and safe.
This project would be suitable for a PhD student or a sub project could be identified for an Honours
student.
Lipid extraction and analysis by mass spectrometry (3)

Cell culture experiments
Animal experiments
References:
1.
Meikle, P. J., G. Wong, D. Tsorotes, C. K. Barlow, J. M. Weir, M. J. Christopher, G. L. MacIntosh, B. Goudey, L.
Stern, A. Kowalczyk, I. Haviv, A. J. White, A. M. Dart, S. J. Duffy, G. L. Jennings, and B. A. Kingwell. 2011. Plasma
lipidomic analysis of stable and unstable coronary artery disease. Arterioscler Thromb Vasc Biol 31: 2723-2732.
2.
Rasmiena, A. A., C. K. Barlow, N. Stefanovic, K. Huynh, R. Tan, A. Sharma, D. Tull, J. B. de Haan, and P. J.
Meikle. 2015. Plasmalogen modulation attenuates atherosclerosis in ApoE- and ApoE/GPx1-deficient mice.
Atherosclerosis 243: 598-608.
3.
Weir, J. M., G. Wong, C. K. Barlow, M. A. Greeve, A. Kowalczyk, L. Almasy, A. G. Comuzzie, M. C. Mahaney, J.
B. Jowett, J. Shaw, J. E. Curran, J. Blangero, and P. J. Meikle. 2013. Plasma lipid profiling in a large population-based
cohort. J Lipid Res 54: 2898-2908.
39
Project title: Plasma Lipid Profiling in Type 2 Diabetes and Coronary Artery Disease
Primary Supervisor (s): A/Prof Peter Meikle
Contact:
8532 1770
monitoring of diabetes and cardiovascular disease (1). This approach is also combined with cell biology
Keywords: Heart disease; atherosclerosis, lipoprotein, lipids, mass spectrometry, biomarker
Project description: Type 2 diabetes and coronary artery disease are major causes of morbidity and
mortality in Australia. A number of lipids and lipoproteins have been identified as useful indicators and
predictors of both type 2 diabetes and atherosclerosis (i.e. cholesterol, HDL, triglycerides). However,
these provide only a restricted picture and a limited interpretation of the disease risk/status of an
individual. It is now becoming clear that many other lipid types are altered during disease onset and
progression and it is likely that some/many of these are involved in disease pathogenesis. We have an
ongoing program of method development and biomarker discovery to identify and validate new lipid
biomarkers of disease (2-4) .
In this project we will use our novel lipidomic approach to generate lipid profiles from patient cohorts at
different stages of disease to identify those lipids and lipid profiles that are specifically associated with
disease onset and progression.
We hypothesize that: the major differences in the plasma lipid profiles between healthy and type 2
diabetes or coronary artery disease precede the clinical presentation and so will be useful to predict
disease outcomes.
1) Perform plasma lipid profiling on patient cohorts that have been clinically phenotyped (type 2
diabetes or coronary artery disease).
2) Determine the plasma lipid profiles that are correlated with the burden of disease and use this to
develop predictive models to identify individuals at increased risk of a disease onset and progression.
The primary outcome of this project will be the development of a plasma lipid profiling test to enable the
early detection of patients at increased risk of type 2 diabetes and coronary artery disease. In addition we
will develop methods to monitor treatment. Identification of individuals prior to the development of
disease will enable early intervention and will have a profound effect on the health of the Australian
population.
This project would be suitable for a PhD student or a sub project could be identified for an Honors
student.
40
Assay development;
Lipid analysis by electrospray ionisation mass spectreometry;
Statistical analysis.
References:
1.
2.
3.
4.
Meikle, P. J., G. Wong, C. K. Barlow, and B. A. Kingwell. 2014. Lipidomics: potential role in risk prediction and
therapeutic monitoring for diabetes and cardiovascular disease. Pharmacol Ther 143: 12-23.
Mamtani, M., H. Kulkarni, G. Wong, J. M. Weir, C. K. Barlow, T. D. Dyer, L. Almasy, M. C. Mahaney, A. G.
Comuzzie, D. C. Glahn, D. J. Magliano, P. Zimmet, J. Shaw, S. Williams-Blangero, R. Duggirala, J. Blangero, P. J.
Meikle, and J. E. Curran. 2016. Lipidomic risk score independently and cost-effectively predicts risk of future
type 2 diabetes: results from diverse cohorts. Lipids Health Dis 15: 67.
Meikle, P. J., G. Wong, C. K. Barlow, J. M. Weir, M. A. Greeve, G. L. MacIntosh, L. Almasy, A. G. Comuzzie, M. C.
Mahaney, A. Kowalczyk, I. Haviv, N. Grantham, D. J. Magliano, J. B. Jowett, P. Zimmet, J. E. Curran, J. Blangero,
and J. Shaw. 2013. Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PLoS
One 8: e74341.
41
Project title: High Density Lipoprotein and Oxidized Lipids in the Prediction of Acute Coronary Syndromes
Primary Supervisor (s): A/Prof Peter Meikle; Prof Bronwyn Kingwell
Contact:
8532 1770
monitoring of diabetes and cardiovascular disease (1). This approach is also combined with cell biology
Keywords: Heart disease; atherosclerosis, lipoprotein, lipids, mass spectrometry, biomarker
Project description: Worldwide more than 19 million people per annum experience a sudden cardiac
event including sudden death, non-fatal myocardial infarction or unstable angina. However, it is still not
possible to accurately identify those at risk of coronary plaque rupture or erosion, the major underlying
causes. This proposal builds on our patented whole plasma lipidomic profile which identified patients
experiencing an unstable or acute coronary syndrome from stable coronary artery disease (CAD) patients
significantly better than conventional risk factors (2).
Our preliminary data shows that atherosclerotic plaque contains a high proportion of oxidized lipids and
that these lipids can be taken up by high density lipoproteins (HDL).
We hypothesize that:
1) Oxidized lipids, produced in plaque, will be exported from plaque into circulation on HDL particles.
2) Lipidomic profiles of HDL incorporating these oxidised lipids will add significantly to traditional risk
factors to better predict future plaque rupture and acute (unstable) coronary syndromes.
In this project we will use tandem mass spectrometry to characterize the lipid composition of
atherosclerotic plaque and identify new lipid markers. Clinically defined patient samples will be used to
isolate lipoproteins from whole plasma using ultracentrifugation. We will then analyse the composition
and distribution of the newly identified lipids across the lipoprotein pools and relate these lipid profiles to
stages of disease.
1) To identify and characterise novel oxidised lipids within carotid endarterectomy specimens.
2) To incorporate these lipids into our high throughput lipidomic assays.
3) To evaluate the lipidomic profile of HDL in patients presenting with stable or unstable CAD.
A secondary aim is to understand the relationship between HDL lipid composition and various aspects of
HDL function in the context of plaque rupture/erosion. These include cholesterol efflux, anti-oxidative and
anti-inflammatory properties. Studies in this area will provide insight into the compelling epidemiological
evidence that HDL is atheroprotective, and establish a basis for identification of biomarkers of both risk
and therapeutic response.
This project would be suitable for a PhD student or a sub project could be identified for an Honors
student.
42
LDL/HDL preparation from plasma

Lipid analysis and characterization by tandem mass spectrometry
HDL functionality assays
References:
1.
2.
Meikle, P. J., G. Wong, C. K. Barlow, and B. A. Kingwell. 2014. Lipidomics: potential role in risk prediction and
therapeutic monitoring for diabetes and cardiovascular disease. Pharmacol Ther 143: 12-23.
43
Project title: Novel strategies to increase energy metabolism in cells as a means to prevent obesity and
type 2 diabetes
Laboratory: Diabetes & Dyslipidaemia Laboratory (DDL)
Primary Supervisor (s) Brian Drew, Anna Calkin
Contact: Brian.drew@bakeridi.edu.au, Ph: 8532 1134
Research Focus: This project focuses on increasing energy production in cells by improving the health of
mitochondria in specific tissues including skeletal muscle, adipose and brain. We will test if this approach
may have benefit in treating diseases including diabetes, obesity and neurodegeneration.
Keywords: energy metabolism, mitochondria, obesity, diabetes, neurodegeneration
Project description: 200-250 words (or less), synopsis of the project, highlighting the main features of the
project (including the potential research question, aim, rationale). Images or graphics maybe added.
Numerous diseases including some cancers, diabetes, obesity and neurodegeneration are associated with
a decline in the health and function of mitochondria small structures within every mammalian cell
responsible for generating energy. However, the cause of this mitochondrial dysfunction - or ways in
which we can prevent or reverse it remain incompletely understood.
In a healthy cell, mitochondria are continuously degraded and regenerated in a tightly controlled cycle
that results in a constant supply of fresh and efficient mitochondria. It is disruption of this tight cycle that
leads to mitochondrial dysfunction. Very little is known about the cellular mechanisms that control this
cycle, even though identification of these mechanisms could have significant therapeutic implications.
To this end, we have recently made some new and exciting findings that identify a number of important
proteins which regulate mitochondrial flux, and also appear to be critical to maintaining mitochondrial
health. Consequently, we have projects available that will test whether manipulation of these proteins in
various tissues (skeletal muscle, adipose tissue, brain) can affect mitochondrial dysfunction in cells and
mice, and therefore affect disease pathogenesis.
Cell culture
qPCR/Western blotting
Oxygen Flux Assays
Cloning, Genetic manipulation
Pre-clinical (mouse) models. Mouse: handling, phenotyping and characterization
References:
1.
Riera CE at al., Nat Cell Biol, 2015
44
Project title:
Novel Regulation of Lipid Metabolism
Laboratory:
Diabetes & Dyslipidaemia
Primary Supervisor (s)
Anna Calkin & Brian Drew
Contact:
anna.calkin@bakeridi.edu.au
8532 1140
Research Focus:
Cell culture and animal studies to validate novel regulators of lipid metabolism identified through our
proteomic/lipidomic discovery platform
Keywords
lipid metabolism, diabetes, cholesterol, triglycerides, insulin resistance, diabetes, steatosis, myocardial
infarction, mice
One is three Australians have elevated cholesterol levels and there is a similar incidence of individuals
with high triglyceride levels. These excess cholesterol and triglycerides can be deposited in tissues such as
the heart, liver and skeletal muscle where they have detrimental effects, promoting atherosclerosis,
cardiac dysfunction, steatosis and insulin resistance. Despite current therapies to lower lipid levels, these
conditions are still major health issues for Australians. Thus, studies are required to identify novel
regulators of lipid metabolism as potential targets for therapeutic intervention.
We provide a novel approach to identify new pathways associated with lipid regulation. This approach is
based on associating the genetic variability across 100 strains of mice with a given phenotype in these
mice (1,2). Specifically, we have linked differences in hepatic protein expression in 100 strains of mice to
changes in plasma and liver lipid levels. Excitingly, this approach has identified many new candidates,
never before linked to lipid metabolism.
This project will involve validation of these identified candidates in liver cells and translation of these
findings to mouse models.
In vitro studies will be performed in the human liver cell lines and will involve genetic manipulation to
overexpress and inhibit a given target and assessment of effects on markers of lipid metabolism.
Animal studies will involve administration of viruses to turn on and off the candidate pathway, followed
by assessment of parameters including plasma and liver lipid levels and lipid signaling pathways.
Cells and tissues will be assessed for metabolic signaling and substrate metabolism using a range of
techniques including qPCR, western blotting and analysis using the Seahorse Bioanalyser and Oroboros.
Immunohistochemical, histological and lipidomic approaches will also be utilised.
Molecular biology cloning, adenovirus, expression constructs, shRNA knockdown

Cell culture liver cell lines, primary liver cells, transfection, infection
Assessment of lipid pathways - qPCR, western blotting, uptake/synthesis/breakdown
Animal studies AAV transduction, metabolic assessment
References:
1. Bennett, et al. A high-resolution association mapping panel for the dissection of complex traits in mice.
Genome Research 2010;20(2):281-90
2. Parks, et al. Genetic control of obesity and gut microbiota composition in response to high-fat, highsucrose diet in mice. Cell Metabolism 2013;17(1):141-52
45
Project title:
IDOL-mediated Regulation of Lipid Metabolism
Laboratory:
Diabetes & Dyslipidaemia
Primary Supervisor (s)
Anna Calkin & Brian Drew
Contact:
anna.calkin@bakeridi.edu.au
8532 1140
Research Focus:
Animal studies to investigate the role of IDOL in the prevention of cardiovascular disease, diabetes and
fatty liver disease
Keywords
lipid metabolism, E3 ligase, diabetes, cholesterol, triglycerides, insulin resistance, diabetes, steatosis,
myocardial infarction, mice
One is three Australians have elevated cholesterol levels and there is a similar incidence of individuals
with high triglyceride levels. These excess cholesterol and triglycerides can be deposited in tissues such as
the heart, liver and skeletal muscle where they have detrimental effects, promoting atherosclerosis,
cardiac dysfunction, steatosis and insulin resistance. Hyperlipidaemia is associated with diabetes, thus
these conditions are commonly observed in these individuals.
IDOL, or Inducible Degrader of the LDL receptor, is a recently identified E3 ligase (1,2). It acts in a
substrate recognition capacity to identify and ubiquitinate its targets in preparation for their
degradation. IDOL has three targets, the LDL receptor (LDLR), the VLDL receptor (VLDLR) and the apoE
receptor (ApoER2), which are involved in the uptake of lipids. We have previously shown that IDOL is
important for the regulation of plasma cholesterol levels in humans (3).
This project will examine whether IDOL can reduce the accumulation of cholesterol or triglycerides in
peripheral tissues and protect against the following,
- lipid-mediated insulin resistance in skeletal muscle
- lipid-induced hepatic insulin resistance
- lipid-induced cardiomyopathy and ischaemia-reperfusion injury
These studies will involve the use of genetically modified mouse models as well as adeno-associated virus
(AAV) to turn on the IDOL pathway in mice. These studies will assess metabolic parameters such as
glucose tolerance and insulin sensitivity. Tissues will be assessed for metabolic signaling and substrate
metabolism using a range of techniques including western blotting, qPCR and analysis using the Seahorse
Bioanalyser and Oroboros. Immunohistochemical, histological and lipidomic approaches will also be
utilised. Mechanistic studies will be performed in cells.
Protein and RNA extraction, western blotting, qPCR, lipidomics
Cell culture, genetic manipulation studies (adenovirus, adeno-associated virus)
Metabolic assays glucose uptake, lipid uptake/synthesis/efflux
Novel mouse models, tissue dissection and analysis, glucose and insulin tolerance tests
References:
1. Zelcer, et al. LXR regulates cholesterol uptake through IDOL-dependent ubiquitination of the LDL
receptor. Science 2009;325;5936:100-4
2. Calkin AC, et al. FERM-dependent E3 ligase recognition is a conserved mechanism for targeted
degradation of lipoprotein receptors. PNAS 2011;108(50):20107-12
3. Weissglas-Volkov D et al. The N342S MYLIP polymorphism is associated with high total cholesterol and
increased LDL receptor degradation in humans. Journal of Clinical Investigation 2011;121(8):3062-71
46
Project title: Diabetes and Heart Failure

Laboratory: Clinical Diabetes and Epidemiology
Primary Supervisor (s): Jonathan Shaw (60%), Tom Marwick (15%), Elizabeth Barr (25%)
Contact:
Research Focus:
Keywords:
Dianna.magliano@bakeridi.edu.au
8532 1826
Diabetes and Heart failure

Diabetes, Epidemiology, heart failure, systematic review
The Clinical Diabetes and Epidemiology group at Baker IDI is focused on studying the epidemiology of
diabetes and its complications. In the past, our group has conducted research on the relationship of
diabetes and/or glucose and cardiovascular diseases such as stroke and myocardial infarction. Recent data
suggests that other types of heart disease may also be related to diabetes, and in particular, evidence is
building to suggest that heart failure may be strongly associated with diabetes. However, clinical care for
people with diabetes primarily focuses on identifying and preventing the development of coronary heart
disease and cerebrovascular disease, as these conditions are common and lead to considerable disability
and premature mortality.
A recent study demonstrated that, in 34,000 people with diabetes heart failure was the second most
common initial cardiovascular disease condition, only surpassed by peripheral arterial disease. This
finding, in which heart failure may frequently precede a clinical manifestation of coronary artery disease,
supports a wealth of research that has described the direct effects of diabetes on the myocardium,
leading to a non-ischaemic cardiomyopathy. However, not all data support this data. There is also little
data on the true burden of heart failure in diabetes. The uncertainty over the burden of heart failure, and
in particular the extent to which it is manifest before other clinical presentations of coronary artery
disease, is of major importance to resolve. We offer a PhD program on diabetes and heart failure which
aims to address some of these issues.
Aims:
To define the burden of heart failure in comparison to myocardial infarction and stroke in people with
diabetes. Specifically:
(i) What is the incidence of diagnosed heart failure among those with diabetes?
(ii) How does the incidence of heart failure compare to that of myocardial infarction and stroke among
individuals with diabetes, and to what extent does this relationship differ by age and sex?
(iii) Establish collaborations to undertake the follow-up of other cohorts for heart failure using data
linkage to hospital and mortality databases.
Masters of public health or equivalent experience

Experience in conducting systematic reviews and/or statistics and epidemiology
47
Project title: Diabetes complications

Laboratory: Clinical Diabetes and Epidemiology
Primary Supervisor (s): Jonathan Shaw (65%), Dianna Magliano (35%)
Contact:
Research Focus:
Keywords
Dianna.magliano@bakeridi.edu.au
8532 1826
Diabetes complications such as chronic Kidney disease

Diabetes, Epidemiology, chronic kidney disease
The Clinical Diabetes and Epidemiology group at Baker IDI is focused on studying the epidemiology of
diabetes and its complications. Our group has recently conducted some data linkages of large Australian
administrative datasets. These include the National Diabetes Service (NDSS) scheme data (the national
diabetes registry) linked to the Australian cancer registry and National death index. We are currently
linking the NDSS to the Australian and New Zealand Dialyses and Transplant registry (ANZDATA), death
index and the pharmaceutical benefit scheme data over the period from 2002-2014. We also have access
to other large datasets and are currently establishing a cohort of 2500 people with diabetes designed to
examine a range of novel biomarkers which may be important in determining progression to diabetes
complications.
We propose a PhD program which has a broad focus on diabetes complications, in particular, chronic
kidney disease using one or more of these datasets.
Objective 1. The starting focus of this program would be to examine non-albuminuric chronic kidney
disease in diabetes and no diabetes. This will be done in several ways. First a systematic review will be
undertaken to understand the current literature on this condition. Then a data analytic approach will be
taken to explore and characterize this condition (in detail) using the CRIC dataset from the US.
Objective 2 will involve examining risk factors for endstage kidney disease in diabetes using the data from
the NDSS-ANZDATA-PBS linkage project.
Objective 3 will involve documenting patterns of medication use among those with diabetic chronic
kidney disease across strata of disadvantage and remoteness in Australia using the linked data.
Objective 4 will be to report on the prevalence of chronic kidney disease in the baseline data of the newly
derived complications cohort.
This program of work is deliberately broad and can be changed to suit the candidates interest.
Masters of public health or equivalent experience

Experience in conducting systematic reviews and/or statistics and epidemiology
A background in therapeutics and pharmacy would be useful.
48
Project title:
Four Projects are under consideration in Imaging research
Laboratory:
Primary Supervisor :
Contact:
Research Focus:
Imaging research
Professor Tom Marwick
lisa.riddell@bakeridi.edu.au
8532 1550
Keywords: echocardiography, ischaemia, atherosclerosis

1) Quality control of echocardiography potential for Honours

Clinical PhD
2) Use of echocardiographic and other markers of ischaemic memory in patients with myocardial
ischaemia
3) Development of a combined method of atherosclerosis and ischaemia detection in patients with
suspected coronary disease
4) Measurement of myocardial deformation as a quantitative tool for stress echocardiography
For project details contact Lisa Riddell at the email or number provided, and she will be able to make a
time for you to speak or meet with Professor Marwick to get further information regarding this project.
49
Project title: Using recombinant antibodies for early diagnosis and treatment of inflammatory diseases.
Laboratory: Thrombosis and Vascular Biology Laboratory
Primary Supervisor (s): Dr Bock Lim & Prof Karlheinz Peter
Contact: Bock.Lim@bakeridi.edu.au 85321447 and Karlheinz.Peter@bakeridi.edu.au 85321490
Research Focus: Using unique single-chain antibodies this project will examine the potential of these
antibodies to target various inflammatory conditions with the aim of generating novel diagnostic tools and
treatment options.
Keywords. Single-Chain antibodies, Platelets, Inflammation, Atherosclerosis, Pulmonary Embolism,
Rheumatoid Arthritis, Multiple Sclerosis, FLECT (FLuorescence Emission Computed Tomography),
Diagnosis, Treatment.
Besides their critical role in haemostasis, platelets are recently associated with immune defense and
inflammation. Activated platelets are shown to play a critical role in various inflammatory diseases such as
atherosclerosis, pulmonary embolism, rheumatoid arthritis and multiple sclerosis. Hence early detection of
these cells during inflammatory progression (diagnosis) and effective inhibition of their function (therapy)
are both critical in the clinical combat against these conditions.
We have generated single chain antibodies which only bind to activated platelets. When linked with a
suitable detector, such as a near-infra red fluorescent probe, this single-chain antibody can be used as
diagnostic marker. The linked protein can be used to detect the presence of
activated platelets in areas of the body where inflammation associating with the
disease is occurring by using a highly specialized, novel and worlds first
FLuorescence Emission Computed Tomography scanner (FLECT). The Figure shows
the detection of fluorescence signal by the scanner in the liver of a mouse.
In addition, when linked to a specific drug, these single chain antibodies can direct
treatment to the site of inflammation where activate platelets are and thereby
reduces drug dosage and undesirable side-effects.
This project will examine the diagnostic and therapeutic capabilities of single-chain
antibodies in the above diseases using different mouse models.
Methods the students will be trained in: Design, production and purification of
recombinant antibodies. Various chemistry and bio-enzymatic reactions for
conjugations. In vitro tests of imaging potential of the generated probes and
therapeutic activity. Ultimately, proof of concept studies in mice using various
models.
Cloning, protein expression and purification

Flow-cytometry and fluorescent microscopy
Various biological and chemistry conjugation techniques
In vivo live animal imaging: FLuorescence Emission Computed Tomography (FLECT) scanning
Various mouse disease models
References:
1. Ta HT, Prabhu S, Leitner E, Jia F, von Elverfeldt D, Jackson K, Heidt T, Nair A, Pearce H, von Zur Muhlen C, Wang X, Peter K,
Hagemeyer CE. Enzymatic single chain antibody tagging: a universal approach to targeted molecular imaging and cell homing in
cardiovascular disease. Circ Res 2011;109(4):365-73.
2. Hohmann JD, Wang X, Krajewski S, Selan C, Haller CA, Straub A, Chaikof EL, Nandurkar HH, Hagemeyer CE, and Peter K. Delayed
targeting of CD39 to activated platelet GPIIb/IIIa via a single-chain antibody: breaking the link between antithrombotic potency
and bleeding? Blood 2013; 121(16):3067-75
3 Wang X, Palasubramaniam J, Gkanatsas Y, Hohmann JD, Westein E, Kanojia R, Alt K, Huang D, Jia F, Ahrens I, Medcalf R, Peter K,
Hagemeyer CE. Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibody-targeted
recombinant plasminogen activator directed against activated platelets. Circ Res 2014;114(7):1083-93.
4. Wang X, Gkanatsas Y, Palasubramaniam J, Hohmann JD, Chen YC, Lim B, Hagemeyer CE, Peter K. Thrombus-targeted theranostic
microbubbles: a new technology towards concurrent rapid ultrasound diagnosis and bleeding-free fibrinolytic treatment of
thrombosis. Theranostics 2016;6(5):726.
50
Project title: Developing Novel Nanoparticles for Clinical Applications: Diagnostic Imaging and Localised
Therapy of Various Diseases
Laboratory: Thrombosis Lab
Primary Supervisor (s): Dr Bock Lim & Prof. Karlheinz Peter
Contact: Bock.Lim@bakeridi.edu.au 85321447, Karlheinz.Peter@bakeridi.edu.au 85321490,
Research Focus: Advancement in nanotechnology has generated many promising particles for clinical
diagnostics and therapeutics. The research will aim to generate, functionalise and test some of these
particles for clinical applications such as Computed Tomography (CT) scan, Magnetic Resonance Imaging
(MRI), Ultrasound, Positron Emission Tomography (PET) and fluorescence imaging, localised therapy and
time-released drug delivery using live mouse models.
Keywords. Nanoparticles, CT, MRI, Ultrasound, Inflammation, Atherosclerosis, Rheumatoid Arthritis,
Cancers, Multiple Sclerosis, Diagnosis, Treatment.
Early detection and effective treatment of pathological diseases are critical in determining the clinical
outcome of patients. These are greatly dependent on the sensitivity and specificity of diagnostic methods
which allow for the application of safe, localised and effective therapies accordingly. Continuous
improvements in these area of existing clinical practice are highly sought-after. Through the study of
nanotechnology, an array of nanoparticles with interesting characteristics has been developed. Their unique
optical, magnetic, thermal and chemical properties can be harnessed for various biomedical applications
such as the development of diagnostic probes with better contrast enhancement, increased sensitivity,
controlled biodistribution, better spatial and temporal information, multi-functionality and multi-modal
imaging across MRI, CT, PET and ultrasound. In additional some nanoparticles showed better in vivo stability
and tissue penetrance which are critical for the effective delivery of drug to diseased sites and some can
even be designed to release therapeutic agents in a time-dependent fashion.
In this project, various promising nanoparticles will be generated,
functionalized to target diseased markers and tested for their abilities to
be used as novel CT, MRI, Ultrasound and fluorescence diagnostic probes
while others for their capability to deliver therapeutic agents. These
nanoparticles will ultimately be assessed using in vivo animal models of
Inflammation, Atherosclerosis, Rheumatoid Arthritis, Cancers and
Multiple Sclerosis. The figure on the right shows one of these
nanoparticles been detected by an imaging scanner following injection
into a mouse. The proposed project is a collaboration between the Baker
Heart and Diabetes Institute and Monash & Melbourne University.
Methods to be learned: Production of nanoparticles (including chemistry). Design, production and
purification of recombinant antibodies. In vitro tests of imaging potential of various nanoparticles.
Ultimately, proof of concept studies in mice.
Cloning, protein expression and purification

Flow-cytometry and fluorescent microscopy
Basic and advance chemistry focusing on nanotechnological synthesis
Various biological and chemistry conjugation techniques
Live whole-body scanning eg CT, MRI, Fluorescence scanning
Various mouse disease models
References:
1. Ta HT, Prabhu S, Leitner E, Jia F, von Elverfeldt D, Jackson K, Heidt T, Nair A, Pearce H, von Zur Muhlen C, Wang X, Peter K,
Hagemeyer CE. Enzymatic single chain antibody tagging: a universal approach to targeted molecular imaging and cell homing in
cardiovascular disease. Circ Res 2011;109(4):365-73.
2. Wang X, Palasubramaniam J, Gkanatsas Y, Hohmann JD, Westein E, Kanojia R, Alt K, Huang D, Jia F, Ahrens I, Medcalf R, Peter
K, Hagemeyer CE. Towards effective and safe thrombolysis and thromboprophylaxis: preclinical testing of a novel antibodytargeted recombinant plasminogen activator directed against activated platelets. Circ Res 2014;114(7):1083-93.
3. Wang X, Gkanatsas Y, Palasubramaniam J, Hohmann JD, Chen YC, Lim B, Hagemeyer CE, Peter K. Thrombus-targeted theranostic
microbubbles: a new technology towards concurrent rapid ultrasound diagnosis and bleeding-free fibrinolytic treatment of
thrombosis. Theranostics 2016;6(5):726.
51
Project title: Diagnosis and therapy of inflammatory diseases using molecular ultrasound imaging
Laboratory: Atherothrombosis and Vascular Biology Lab
Primary Supervisor (s): Dr. Xiaowei Wang & Prof. Karlheinz Peter &
Contact: Karlheinz.Peter@bakeridi.edu.au 85321490, xiaowei.wang@bakeridi.edu.au 85321495
Research Focus: Research in the Atherothrombosis and Vascular Biology lab focuses on translational
research that links basic science to the clinical application, thereby enhancing human health and wellbeing. Molecular ultrasound imaging allows for early diagnosis and therefore timely and appropriate
therapy.
Keywords. Single-Chain antibodies, Inflammation, Molecular Imaging, Ultrasound
The use of small recombinant antibodies for diagnostic molecular ultrasound imaging and
targeted drug delivery is well established in our lab1-3. Ultrasound imaging offers significant advantages: It
is already a well established clinical imaging technique and the equipment required is already available in
most hospitals. It is non-invasive, cost effective, real-time and does not involve ionising irradiation. There
is no known long-termed side effect of ultrasound imaging. Ultrasound imaging is well suited for routine
clinical application where frequent imaging is needed, such as in A broad screening program for early
disease detection. In addition, contrast enhanced ultrasound with bubbles has been successfully
introduced into the clinic and there is a high probability that our targeted microbubble approach can be
rapidly translated into clinical practice.
This project would focus on imaging of inflammatory conditions. Peritonitis is the inflammation of
the abdominal cavity and a serious clinical complication after the rupture of organs upon abdominal
trauma or appendicitis. Optimised early therapy of these conditions is hindered by the lack of fast, realtime imaging technologies. Molecular imaging has the potential to provide early diagnosis thereby
allowing timely therapy and prevention of sepsis.
One of the endothelial surface molecules most strongly and specifically upregulated in
inflammation is the Vascular Cell Adhesion Molecule-1 (VCAM-1). For this reason this molecule has been
chosen as an additional target epitope for molecular imaging of inflammation. We propose to conjugate
VCAM-1 targeting recombinant antibodies to ultrasound contrast agents for imaging via contrast
enhanced ultrasound. We would use this recombinant antibody for diagnosis imaging and targeted
delivery of pharmacological treatment.
Significance: With steadily increasing health care expenses, a promising translational imaging application
using ultrasound can fulfil the need for a cost-effective and non-invasive diagnostic tool.
Production of recombinant proteins for diagnosis and therapy

SDS PAGE and Western blots
Flow cytometry
Generation of functionalized imaging contrast agents
Ultrasound imaging
Animal models
References:
1. Wang, X.,.... Peter, K. & Ahrens, I .Circulation 2012; 125: 3117-3126.

2. Wang, X.,.... Peter, K. & Hagemeyer CE. Circulation Research, 2014; 114:1083-1093
3. Hohmann, JD., Wang, X.,.... & Peter, K. Blood 2013; 121: 3067-3075.
52
Project title: Activated platelet-targeted drug therapy.

Primary Supervisor (s):Prof. Karlheinz Peter &Dr. Xiaowei Wang
Research Focus: Research in the Atherothrombosis and Vascular Biology lab focuses on translational
research that links basic science to the clinical applications that enhance human health and well-being.
Targeted drug delivery allows effective thrombolysis and the potential novel use as a fibrinolytic agent
without bleeding complications.
Keywords. Single-Chain antibodies, Thrombolysis, Treatment, Targeted drugs delivery
Acute thrombosis causing vessel occlusion and resulting in ischemic complications such as
myocardial infarction and stroke is a major cause of death and disability.
Fibrinolysis is a valuable alternative for the treatment of myocardial infarction when
invasive/surgical procedure is not available in a timely fashion. For acute ischemic stroke, fibrinolysis
is the major treatment option with a very narrow therapeutic window. Clinically approved
thrombolytics have significant drawbacks, including bleeding complications. Thus their use is highly
restricted leaving many patients untreated. The use of small recombinant antibodies for diagnostic
molecular ultrasound imaging and targeted drug delivery is well established in our lab1-3.
This project would focus on the development of novel targeted fibrinolytic drug that is directed against
activated platelets3.
When thrombosis occurs, there will be a thunderstorm of platelet activation and aggregation. Our
targeted fibrinolytic drug will locate these activated platelets and accumulate at the site of the clot. This
allows a high potency of drugs for efficient and safe thrombolytic treatment. Due to the targeting
properties, we can reduce the overall amount of drugs need, thereby there would only be a small
concentration of drugs circulating in the blood. This would also enable us to eliminate the current
bleeding complications associated with the clinically used fibrinolytic drugs.
Significance: This novel fibrinolytic agent promises to overcome the current limitations in thrombolytic
therapy associated with the risk of bleeding complications. It has the potential to break the fatal
link between increased fibrinolytic potency and bleeding complications.

Flow cytometry
Ultrasound imaging
Animal models
References:

53
Project title: Molecular ultrasound imaging of thrombotic diseases using activated platelet-targeted
microbubbles
Primary Supervisor (s):Prof. Karlheinz Peter &Dr. Xiaowei Wang
Research Focus: Despite primary and secondary prevention, thrombotic and embolic events such as myocardial infarction and stroke remain a major health issue and are leading causes of mortality and morbidity
in Australia and worldwide. Research in the Atherothrombosis and Vascular Biology lab focus on
translational research that links the findings from basic science to the practical applications that enhance
human health and well-being in the clinical settings. Molecular ultrasound imaging of thrombi/emboli
would allow for early diagnosis and therefore timely and appropriate medical intervention
Keywords. Single-Chain antibodies, Platelets, Diagnosis, Thrombosis, Treatment.
Our lab has extensive experience with small recombinant antibodies that binds to the activated
platelets on thrombi1. When these antibodies are coupled to contrast agents, we
could use them for diagnostic imaging and monitoring of treatment2,3. In
addition, these antibodies could be coupled to thrombolytic drugs and be used
for targeted therapy, thereby avoiding the bleeding complications3,4.
We have showed that these antibodies, when conjugated to microbubbles,
could be use them for molecular ultrasound imaging of thrombotic diseases2,3.
Figure shows the increase binding of targeted microbubbles (LIBS-MB) to the
thrombus in the carotid artery of mice.
Our current aim to use this technology to image several other thrombotic
disease models, such as venous thrombosis, atrial fibrillation, atherosclerosis
(plaque instability) and myocardial infarction.
Significance: With steadily increasing health care expenses, a promising
translational imaging application using ultrasound can fulfil the need for a costeffective and non-invasive diagnostic tool, thereby reducing the mortality and
morbidity of cardiovascular diseases.

Flow cytometry
Ultrasound imaging
Animal models
References:
1. Hagemeyer CE, Peter K.Curr Pharm Des 2010, 16:4119-4133

54

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BakerIDI Student Research Projects 2017

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STUDENT RESEARCH PROJECTS

Addressing the changing health

Baker IDI Heart and Diabetes Institute is an

Project related methods/skills/technologies:

Project related methods/skills/technologies:

1. Jackson, K. L., F. Z. Marques, A. M. Watson, K. Palma-Rigo, T. P. Nguyen-Huu, B. J. Morris, F. J. Charchar, P. J. Davern

Phone: 8532 1565

Project related methods/skills/technologies:

Research Focus: Diabetic nephropathy, mitochondrial dysfunction

Project related methods/skills/technologies:

Project title: The role of let 7 micro-RNA in atherosclerosis: endothelial cells

Laboratory: Genes and Diabetes (Diabetic Complications Laboratory)

Laboratory: Genes and Diabetes (Diabetic Complications Laboratory)

RNA isolation techniques

Project title: Lipoxin A4 analogues as a treatment for diabetic nephropathy

Laboratory: Genes and Diabetes (Diabetic Complications Laboratory)

Project related methods/skills/technologies:

Project title: The role of phospholipids in macrophage polarization

Keywords: macrophage polarization, phospholipids, inflammation

Blood monocyte isolation and cell culture

Keywords: heart failure, fibrosis, tilorone, novel therapies

Project related methods/skills/technologies:

Experimental mouse procedures (echocardiography, dissection, i.p. injections)

5. Zeisberg et al., 2003 Nat Med 9:964-8

Project title: The role of the microRNA miR-181a in blood pressure

Animal models and surgeries

Project related methods/skills/technologies:

Cell culture validation

Using multiple mouse

Project related methods/skills/technologies:

Cell culture validation

Using multiple mouse

Project title: Regulation of skeletal muscle mass in health and disease

Fig1. Schematic of rAAV production and

Fig2. Schematic representation of the human

Project related methods/skills/technologies:

Project title: Development of brown adipose tissue for treatment of obesity

Project related methods/skills/technologies:

Project related methods/skills/technologies:

Exercise (30-minutes) + uninterrupted sitting

Exercise (30-minutes) + interrupted sitting (3-minute walk/every 30-minutes)

Laboratory experiments (radioimmunoassay)

Laboratory experiments (radioimmunoassay)

Good clinical practice

Retinal scans will be taken at baseline and 5-hours.

Project title: New Cellular Cholesterol Transporter

Reverse Cholesterol Transport Pathway

Project related methods/skills/technologies:

Project title: Novel Pathogenic Mechanisms of HIV-Associated Neurocognitive Disorder

Project related methods/skills/technologies:

Project title: Cholesterol metabolism and complications of HIV disease

Project related methods/skills/technologies:

Project title: Plasmalogen modulation as a treatment for atherosclerosis

We hypothesize that: Upregulation of plasmalogens

The specific aims are to:

Lipid extraction and analysis by mass spectrometry (3)

Project related methods/skills/technologies:

Project related methods/skills/technologies:

LDL/HDL preparation from plasma

Riera CE at al., Nat Cell Biol, 2015

Molecular biology cloning, adenovirus, expression constructs, shRNA knockdown

Project title: Diabetes and Heart Failure

Diabetes and Heart failure

Masters of public health or equivalent experience