Anti-apoptotic Mechanism of SF/HGF Mimetics
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AbstractDESCRIPTION (provided by applicant): Apoptotic cell loss triggered by ischemia-reperfusion plays a prominent role in delayed graft function and acute renal failure following kidney transplant. In experimental models of ischemia-reperfusion, treatment with scatter factor/hepatocyte growth factor reduced renal dysfunction and accelerated renal regeneration, in part by attenuating apoptotic cell death. Using phage display technology and molecular modeling we recently identified C6, a small molecule compound, which exhibits scatter factor/hepatocyte growth factor-like cytoprotective effects. Small pilot studies suggest that the anti-apoptotic effect of C6 is mediated by nitric oxide. By delineating the signaling pathways involved in C6 cytoprotection, the proposed SBIR Phase I application can lead to the development of new C6 analogs that specifically target these pathways, maximizing therapeutic potential while minimizing the risk of any side effects. These studies are expected to provide sufficient supporting data for more in depth Phase II studies with the ultimate goal of bringing this compound or other more potent and easily deliverable compounds into clinical trials for the treatment of renal failure.
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