Long term objectives: In general, apoptosis can be induced either by the presence of an apoptotic stimulus (e.g.Fas or cell injury) or by the absence of so-called survival factors. Most if not all cells require survival signals to continuously suppress apoptosis. In the absence of these survival signals, cells undergo apoptosis. The """"""""default pathway"""""""" refers to apoptosis induced exclusively by the absence of survival factor(s). The overall goal of this application is to focus exclusively on the role played by the default pathway of apoptosis in the pathogenesis of ischemic acute renal failure (ARF). The application will focus on two novel survival factors for proximal tubular cells in ARF. The first is the lipid growth factor lysophosphatidic acid (LPA), and the second is cadherin dependent cell-cell adhesion. Hypotheses: The default pathway of apoptosis contributes to the pathogenesis of ARF via two important and independent mechanisms: 1) LPA represents an important soluble survival factor for tubular cells and a deficiency of LPA contributes to apoptosis of these cells in ARF. 2) cadherin-dependent cell-cell interactions between exfoliated renal tubular cells acts as a survival signal to inhibit the default pathway of apoptosis in these exfoliated cells. The survival of viable renal tubular cells shed into the tubular lumen may be deleterious to the course of ARF, by promoting the formation of obstructive intratubular casts. Significance (health relatedness): ARF is a common clinical problem that, despite optimal treatment, still has a mortality of approximately 50%. This application is directed at understanding the pathogenesis of ARF and developing novel therapies for this disease.
Specific Aims. 1) to elucidate the signaling pathways and/or intracellular mediators by which LPA activates PI3K and mediates proliferation and inhibition of the """"""""default pathway"""""""" of apoptosis. 2) to elucidate the signaling pathways and/or intracellular mediators by which cadherin-dependent cell- cell interaction between renal tubular cells mediates PI3K activation and inhibition of the """"""""default pathway"""""""" of apoptosis. 3) to examine the role of both of these """"""""default pathway"""""""" of apoptosis in the pathogenesis of ischemic ARF.
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