The dynamic interactions between cellular-molecular physiology and the environment - case studies in pathophysiology - how to exploit cellular-molecular evolution

Published on May 31, 2016   8 min

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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.
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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.
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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.
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Similarly, hyperoxic exposure simplifies the alveoli in this study, an effect normalized by the PPAR gamma agonist rosiglitazone, or RGZ.
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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.
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The dynamic interactions between cellular-molecular physiology and the environment - case studies in pathophysiology - how to exploit cellular-molecular evolution

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