27,
2016
Dr.
Gonzalo
B.
Roman
│
The
Cell
as
a
Unit
of
Health
&
Diseases
│
Pathology
• Pathos
–
“suffering”
• NON-‐CODING
REGIONS
• Pathology
–
Study
of
Suffering
/
Diseases
§ “architectural
planning”
• Virchow
–
coined
Cellular
Pathology;
all
diseases
§ specifies
specificity
originate
at
a
“cellular
level”
• Gene
interaction
dictates
SPECIFIC
TRAITS
AP
walk
–
slang
for
a
slouched
walk
for
a
person
with
(PHENOTYPE)
appendicitis
a) Promoter,
enhancer
regions
(binding
sites
for
transcription
I.
THE
GENOME
factors)
• The
gene
complement
of
an
organism
(genes
specific
b) Binding
sites
for
factors
that
for
a
physical
trait
or
disease)
organize
&
maintain
higher
order
• Genomic
mapping
chromatin
structures
o assignment
of
genes
to
specific
c) Non-‐regulatory
RNAs
(miRNA
&
chromosomes
lncRNA)
• Human
Genome
Project
d) Transposons
(jumping
genes)
o International
project
to
identify
&
localize
e) Telomeres
(chromosome
ends)
&
the
over
30,000
estimated
genes
in
the
centromeres
(tethers)
human
genome
o The
human
genome
contains
roughly
3.2
• Humans
&
chimpanzees
share
99%
of
their
DNA
Billion
DNA
base
pairs
[on
1
small
nucleus]
sequence
o Within
the
genome,
there
are
about
20,000
• Any
2
individuals
share
>99.5%
of
their
DNA
protein-‐coding
genes,
comprising
only
about
sequences
1.5%
of
the
genome.
o The
remaining
0.5%
represents
person-‐to-‐
person
variation,
differential
susceptibility
to
In
other
words:
diseases,
and
in
response
to
environmental
Human
Genome
(3.2B
DNA
base
pairs),
1.5%
of
that
human
agents
&
drugs.
genome
is
comprised
of
20,000
protein-‐coding
genes.
o 0.5%
represents
about
15million
base
pairs
The
protein-‐coding
genes
will
produce
enzymes,
structural
components,
&
signaling
molecules
• DNA
Variation
(0.5%)
Most
Common
a. Single
Nucleotide
Polymorphism
(SNP)
o Interaction
of
several
genes
is
required
to
§ 6
Million
known
SNPs
manifest
a
certain
trait,
provided
with
the
§ Variants
at
a
single
nucleotide
appropriate
environment.
positions
o DNA
Base
Pairs:
A-‐T
&
G-‐C
o Nucleotide
–
3
pairs
o Any
cell
with
a
NUCLEUS
contains
a
genome
§ Biallelic
(only
2
choices
exist
at
a
§ RBCs
don’t
have
a
nucleus,
so
they
don’t
given
site
within
the
population,
have
a
genome.
such
as
A
or
T)
§ Occurs
within
exons,
introns,
WORMS
• Contains
<1,000
cells
with
genomes
of
only
about
intergenic
regions,
&
coding
regions
0.1
Billion
DNA
o 1%
occur
at
coding
regions
o Also
assembled
using
20,000
genes
that
o Non
coding
regions
are
regulatory
produce
proteins
(same
as
humans)
elements
for
gene
expression
• What
differs
them
from
humans
lies
in
the
98.5%
§ In
other
instances,
SNPs
may
be
part
of
the
human
genome
that
DOESN’T
ENCODE
neutral
variant
that
has
no
effect
on
PROTEIN
gene
function
or
carrier
phenotype.
o d/t
genomic
blueprints
rather
than
construction
materials
§ Its
effect
on
disease
susceptibility
is
WEAK
–
it
is
useful
as
a
marker.
o 80%
of
the
human
genome
either:
b. Copy
Number
Variation
(CNV)
1. Binds
proteins
§ Large,
continuous
stretches
of
DNA
Ø Implying
it
is
involved
in
gene
from
1000
base
pairs
to
millions
of
regulation
base
pairs
2. Assigned
some
functional
§ Biallelic
Ø Mostly
related
to
regulation
of
§ CNVs
are
responsible
for
between
gene
expression
(cell-‐type
5-‐24
million
base
pairs
of
sequence
specific
fashion)
difference
in
any
2
individuals
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Page
1
June
27,
2016
Dr.
Gonzalo
B.
Roman
│
The
Cell
as
a
Unit
of
Health
&
Diseases
│
Pathology
§ 50%
of
CNVs
are
gene
coding
II.
CELLULAR
HOUSEKEEPING
sequences
(determines
phenotype
• Environmental
protection
diversity
–
RACES)
(plasma
membrane)
• Nutrient
acquisition
• Histone
Organization
(Glucose
-‐>
oxygen)
o DNA
is
a
spherical
helix
which
would
around
• Communication
a
HISTONE
(interleukines)
o DNA-‐HISTONE
complex
resembles
a
series
of
• Movement
beads
(“prayer
beads”
according
to
Dr.
Ric).
This
is
(growth;
skin
-‐>
basal
cells
-‐>
now
called
a
NUCLEOSOME
para/intermediate/surface
-‐>
cornified
or
o Nucleosome
with
DNA
linkers
then
form
keratinized/dead
cells)
CHROMATIN
• Renewal
of
senescent
molecules
o [DNA
+
HISTONE
=
NUCLEOSOME
-‐>
CHROMATIN]
(mitochondria)
by
protein
blocks
o Types
of
Chromatin
• Molecular
catabolism
a. Heterochromatin
(waste
products
mgmt.)
• Inactive
• Energy
generation
• Compact
(wound)
b. Euchromatin
Proteins
• Active
o From
Rough
ER
• Dispersed
(unwound)
o Assembled
at
Golgi
apparatus
(further
refined)
• Gene
expression
a.
Lysosomes
–
(+)
degradative
enzymes
• Micro
RNA
(miRNA)
&
Long
Noncoding
RNA
b.
Proteasomes,
Peroxisomes
-‐
specific
degradation
(lncRNA)
c.
Endosomal
vesicles
–
shuttles
internalized
material
o Gene
regulation
depends
on
NONCODING
d.
Cytoskeleton
–
for
cell
mov’t,
shape,
&
IC
organization
RNAs
*Columnar
cells
–
determines
polarity
o They
are
encoded
by
genes
that
are
e.
Mitochondrion
–
ATP
production
d/t
Oxidative
TRANSCRIBED
but
not
TRANSLATED
Phosphorylation
1. miRNA
1.
Plasma
Membrane
o Fluid
ampiphatic
bilayers
of
phospholipids
with:
• short
RNAs
(22
nucleotides)
§ Hydrophilic
head
groups
§ Do
not
encode
proteins
o Loves
water;
faces
ECM
§ Modulate
translation
of
target
§ Hydrophobic
tails
mRNAs
into
their
corresponding
o Hates
water;
barrier
for
proteins
large/charged
molecules
§ Functions
in
gene
regulation
by
*Lipid
layer
–
BARRIER!
posttranscriptionally
silencing
gene
o (+)
heterogenous
different
phospholipids;
expression
Asymmetrical
distribution
2. lncRNA
o Proper
distribution
=
good
health
• modulates
gene
expression
in
many
ways:
a.
P.
inositol
–
electrostatic
scaffold
@
inner
leaflet
o gene
activation
b.
P.
serine
–
inner
-‐>
outer
=
APOPTOSIS
signal
o suppression
c.
Glycolipids
&
Sphingomyelin
–
EC
face;
Cell-‐to-‐cell
o increases
chromatin
&
cell-‐ECM
interactions
modification
o (+)
protein
complexes
o Some
components
CONGLOMERATE
/
MOVE
TOGETHER
(like
lipids)
-‐>
“lipid
raft”
o Proteins
+
Glycoproteins:
§ Ion
&
metabolite
transport
§ Receptors
§ Ligands
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PROPERTY
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2019
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OWN
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Page
2
June
27,
2016
Dr.
Gonzalo
B.
Roman
│
The
Cell
as
a
Unit
of
Health
&
Diseases
│
Pathology
2.
Cytoskeleton
• Biosynthetic
Machinery:
Golgi
Apparatus
&
ER
o Shape,
polarity
(apical/basal
membrane),
relationship
o Production
(ribosomes)
=
Degradation
of
IC
organelles,
mov’t
(lysosomes)
o Classes:
• ER
–
transmembrane
CHON,
organelle
a.
Actin
microfilaments
production
§ 5-‐9nm
diameter
• Golgi
App
§ from
G-‐actin
(globular)
-‐>
long
polymerize
F-‐ o (+)cisternae
-‐>
modifies
CHON
in
a
(cis-‐
actin
trans
way)
§ e.g.,
myosin
+
actin
-‐>
mov’t
d/t
ATP
o increased
in
cells
for
secretions
(GIT,
hydrolysis
[CONTRACTION]
Pancreas,
ovary,
testis,
thyroid,
PTH
organ)
b.
Intermediate
filaments
• Lysosomes
§ 10nm
d.
o (+)enzymes
for
denaturation
§ Lamin
A,
B,
C
o 40
diff.
acid
hydrolases
(even
§ Vimantin
(mesenchymal,
BACTERIA):
proteases,
nucleases,
chondro/fibroblasts)
lipases,
glycosidases,
phosphatases,
etc.
§ Desmin
(muscle
cells)
• Proteases
§ Neurofilaments
(axons)
o Cytosolic
protein
(even
cell
itself)
-‐>
d/t
§ Glial
Fibrillary
Acidic
Protein
severe
infection
o Identify
tumor
cell
specificity
(bone,
• Mitochondria
neuron,
etc.)
o Power
plant
(ATP
production
&
storage)
o Special
stain
o Organic
compounds
-‐>
energy
for
cell
§ Cytokeratins
itself
o 30
distinct
varieties
o (+)
enzymes
for
collecting
food
stuffs
-‐>
o epithelial
cells
(squamous
cells)
skin
convert
to
energy
o Energy
not
used/stored
is
dissipated
as
c.
Microtubules
HEAT
to
maintain
constant
body
temp.
§ 25nm
thick
o Contain
their
own
DNA
&
ribosomes
for
§ alpha
&
beta
tubulin
non
covalent
polymers
self-‐replication
§ moves
vesicles,
organelles,
or
other
§ Mitochondrial
DNA
–
13;
for
function;
molecules
around
cells
along
microtubules
maternal
inheritance
using
ATP
§ Nuclear
DNA
–
for
structure
§ Cell-‐to-‐cell
Interaction
III.
CELL
DEATH
o (+)
mechanical
links
from
junctions
• Mitochondria
regulates
balance
of
cell
survival
&
death
a.
Occluding
(tight)
• 2
Major
Pathways:
§ Blood
brain
barrier
–
prevents
passage
of
molecules;
increase
dosage
to
allow
1. Necrosis
diffusion
of
antibiotics
• d/t
EC
injury
(toxins,
ischemia,
trauma)
b.
Anchoring
(desmosomes)
-‐>
increased
mitochondrial
permeability
§ Seen
at
light
microscope
-‐>
mitochondrial
damage
-‐>
proton
§ Squamous
+
squamous
potential
disruption
-‐>
(-‐)
ATP
§ extracellular
bridges
production
-‐>
cell
death
c.
Communicating
(gap)
2.
Apoptosis
§ tissue
pores
• intrinsic
(by
mitochondria)
/
extrinsic
stimuli
#DarthVADR
PROPERTY
OF
AUF
SOM
BATCH
2019
USE
AT
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OWN
RISK!
Page
3
June
27,
2016
Dr.
Gonzalo
B.
Roman
│
The
Cell
as
a
Unit
of
Health
&
Diseases
│
Pathology
IV.
CELL
ACTIVATION
• Growth
Factors
EC
signal
–
it
lives
or
dies,
grow
or
regress
o Increased
at
pituitary,
some
are
at
local;
for
Signals
cell
growth
&
division
o chemicals
(if
injurious,
there
will
be
enzymes
to
§ Promote
entry
of
cell
at
cell
cycle
increase
protection),
CHONs
§ Blocks
cell
cycle,
progression
(for
o for
adaptive
response
to
various
threats
promoting
replication)
• local
trauma
§ Apoptosis
o punched
by
Manny
Pacquiao
-‐>
§ Biosynthesis
of
cell
components
black
eye
(hematoma
(normal
proportion)
formation)
-‐>
prevents
spread
o e.g.,
Epidermal
GF,
Hepatocyte
GF,
Platelet
è ADAPT
GF,
Vascular
GF,
Fibroblast
GF,
Transforming
• Systemic
infection
GF
–
beta
o Tonsil
infection
-‐>
spread
-‐>
septicemia
VI.
INTERACTION
WITH
ECM
• Loss
of
communication
-‐>
unregulated
growth
-‐>
• Network
of
interstitial
proteins
CANCER
• For
development,
healing
&
maintaining
tissue
architecture
• Cell
Signaling
o Differentiates,
proliferates
• ECM
• d/t
damage
to
neighboring
cells
&
o Mechanical
support
pathogens
o Scaffolding
for
tissue
renewal
&
• contact
inhibition
(neighboring
cells)
microenvironment
• contact
with
ECM
o 2
Forms:
• secreted
molecules
a. Interstitial
Matrix
o e.g.,
thyroid
only
responds
to
TSH
d/t
• Type
1,2,3,5
collagen
special
receptors
(skin
doesn’t
respond
• Between
cells;
by
mesenchymal
to
TSH)
cells
o damaged
cells
-‐>chemical
mediators
-‐>
b. Basement
Membrane
vasoconstriction,
attraction
of
WBCs
• Where
cell
sits;
gives
organization
(cells
grow
only
a. Paracrine
s.
–
surrounding
cells
upward)
b. Autocrine
s.
–
self/same
cell
type
• By
Type
4
nonfibrillar
collagen
c. Synaptic
s.
–
neurons
-‐>
inc.
NTs
&
laminin
d. Endocrine
s.
–
bloodstream
(hormones)
EXCEPTION:
CANCER
CELLS
(invades
Basement
Membrane)
-‐>
grows
V.
SIGNAL
TRANSDUCTION
PATHWAYS
(CELL
SIGNALING)
downward
-‐>
invades
blood
vessels
&
lymphatics
-‐>
• Signal
transduction
–
(+)
molecular
signals
[EC
to
IC]
metastasis
*Signal
-‐>
(+)
response
*without
it,
it
is
useless
*NORMAL
CELLS
don’t
ivade
basement
membrane
J
• Cellular
Receptors
VII.
MAINTAINING
CELL
POPULATIONS
o Receptors
with
associated
kinase
activity
• Cell
Proliferation
§ Receptor
Tyrosine
Kinase
(RTKs)
o for
homeostasis
&
replacement
of
o (-‐)
Intense
Catalytic
activity
(immune
dead/damaged
cells
receptors,
cytokine
receptors,
integrins)
• Key
elements
o G-‐protein
coupled
receptors
o Accurate
DNA
replication
(for
normal
cell
o Nuclear
receptors
growth)
followed
by
equal
apportionment
of
o Others:
Notch
family
&
Wnt
ligands
DNA
&
other
cellular
constituent
to
daughter
cells
#DarthVADR
PROPERTY
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AUF
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2019
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OWN
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Page
4
June
27,
2016
Dr.
Gonzalo
B.
Roman
│
The
Cell
as
a
Unit
of
Health
&
Diseases
│
Pathology
• Cell
cycle
G1
–
presynthetic
growth
§
S
–
DNA
synthesis
§
G2
–
premitotic
growth
§
M
–
mitotic
phase
§
G0
–
quiescent
cells
not
actively
§
cycling
o Regulated
by
activators
&
inhibitors
o Driven
by
CYCLINs
(>15)
D,
E,
A,
B
o Surveillance
mechanism
• Sense
DNA/chromosome
damage
-‐>
signals
apoptosis
• If
it
fails
-‐>
TUMOR
• “quality
control”
• Stem
Cells
o various
differentiated
tissues
o ADULTS:
• replace
damaged
cells
&
maintain
tissue
population
• dies
d/t
shortening
of
telomeres
o 2
Properties:
• Self-‐renewal
–
maintains
their
numbers
• Asymmetric
distribution
o 2
Varieties:
a.
Embryonic
SC
• most
UNDIFFERENTIATED
(no
specificity)
• @
inner
cell
mass
of
blastocyst
• limitless
capacity
(totipotent)
b.
Tissue
SC
• adult
stem
cells
• produce
cells
that
are
normal
constituents
of
that
tissue
Regenerative
Medicine
(Promising;
still
under
research)
o stem
cells
to
repopulate
damaged
tissues/construct
an
entire
organ
(Alzheimer’s
dse,
MI)
o e.g.,
Myocardial
Infarction
-‐>
decreased
cardiac
cells
-‐>
(+)
stem
cells
-‐>
increased
cardiac
cells
o known
to
be
successful
in
Bone
Marrow
Transplant
after
chemotherapy
(hematopoietic
stem
cells
for
leukemia)
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5