Protection from Fas-mediated apoptosis in the gut

Project: Research project

Project Details


DESCRIPTION (adapted from the application)
This application for an RO3 is to serve as a supplement to K08
DK02635‑03. The title of the original K08 is "Growth and Death Signals in
the Prostate". As a gastroenterologist, my clinical and research focus is
inflammatory bowel disease. Specifically, I am interested in intestinal
epithelial cell apoptosis and its role in barrier dysfunction in the inflamed
intestine. Because of that interest, I chose Dr. Charles Sawyers as my mentor
for the K08. Although seemingly disparate systems, the research in Dr. Sawyers'
laboratory on prostate cell apoptosis has given me the tools to transition back
to the intestinal tract and further an understanding of intestinal epithelial
cell apoptosis as it relates to inflammation. The experimental strategies
described in this proposal build upon my post‑doctoral experience in the
laboratory of Dr. Sawyers utilizing genetic strategies to define signaling
pathways and my experience in studying intestinal epithelial cell apoptosis and
its effects on barrier function. During the initial two years of the K08, I
completed a study examining the role of MEKK1 in androgen receptor signaling
and described an important, previously unknown interplay between the MEKK
pathway and androgen receptor transcriptional regulation (Abreu‑Martin et
al. 1999). I have also developed a model of Fas‑mediated apoptosis and
its effect on intestinal barrier function (Abreu et al. 2000). The results of
our studies suggest that the intestinal epithelium is quite resilient in the
face of immune-mediated apoptosis because the remaining epithelial cells
dramatically restructure their tight junctions and maintain E-cadherin-mediated
cell contact to prevent holes in the monolayer. I am now poised to merge these
two areas of research in this proposal entitled PI3'-kinase-dependent
protection from Fas-mediated apoptosis in the gut: role in maintenance of
barrier function." We will test the hypothesis that PI3'-kinase-dependent
mechanisms protect intestinal epithelial cells from Fas-mediated apoptosis and
barrier dysfunction. Preliminary data demonstrates [sic] that inhibition of
PI3'-kinase dramatically sensitizes intestinal epithelial cells to Fas-mediated
apoptosis and barrier dysfunction. Expression of constitutively-active Akt, an
important kinase downstream of PI3'-kinase, protects against Fas-mediated
apoptosis. Moreover, cross-linking of Fas leads to phosphorylation of Akt
suggesting activation of a survival pathway in addition to a death pathway. Our
specific aims will trace the protective effect of PI3'-kinase from the plasma
membrane to the nucleus. The results of this study have implications for the
medical therapy of inflammatory bowel disease. These diseases are manifested by
immune-mediated destruction of the lining intestinal epithelial cells. The
support from this R03 will permit me to successfully compete for an R01 and
make the transition to an independent investigator.
Effective start/end date7/1/016/30/03


  • National Institute of Diabetes and Digestive and Kidney Diseases: $76,500.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $76,500.00


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