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My name is John Torday.
I am a professor of evolutionary
medicine at UCLA.
This lecture is entitled
Case Studies in Pathophysiology,
how to exploit
cellular-molecular evolution.
0:13
Many chronic diseases
are characterized
by a simplification
of structure and function.
This simplification process
is associated
with the loss of differentiated
growth factor receptor signaling
and a gain
of signaling characteristic
of an earlier developmental
and/or phylogenetic phase.
This phenomenon is traditionally
interpreted as inflammation,
because it is associated
with scarring.
Such data also suggests
a regression of the tissue
towards an earlier stage
in its evolution,
the inflammation resulting
from loss of homeostatic control
as a result,
not a cause of the disease.
If that is that case,
then in theory,
structure and function
could be restored
by driving the tissue back
in the forward direction
to reestablish homeostasis
and effectively treat disease.
0:59
For example,
chronic lung disease
induced by oxygen exposure
is associated
with simplification,
as shown by the histograms
on the far right
measuring alveolar septation
and wall thickness.
On the right is shown
the increase
in Wingless/Inter
"Wnt" signaling
in the alveoli characteristic
of both inflammation
and simplification of the lung.
Treatment with
an anti-inflammatory agent,
such as curcumin,
normalizes this condition.
1:26
Similarly, hyperoxic exposure
simplifies the alveoli
in this study,
an effect normalized
by the PPAR gamma
agonist rosiglitazone, or RGZ.
1:36
In this slide, we see
the normal kidney glomerulus
on the left
and the scarred
or sclerotic glomerulus
on the right.
The sclerotic glomerulus
is characterized
by increased deposition
of matrix
within the mesangium,
a supporting structure
for the microcirculation
of the glomerulus
that regulates fluid
and electrolytes,
reaching to the kidney tubule.
The scarring of the mesangium
is due to the breakdown
in PTHrP signaling
from the podocytes
lining the glomerulus,
which monitors fluid pressure
within the glomerulus.
PTHrP signaling maintains
the differentiated state
of the mesangial fibroblasts.
When PTHrP signaling fails
due to injury to the podocytes,
the mesangial fibroblasts
default
to their myofibroblast
phenotype,
which deposits
extracellular matrix
in the scarring process.
