RNA interference (RNAi) is a mechanism of gene silencing originally described in plants and invertebrates and more recently in mammalian cells. This Fogarty proposal will study specific applications of RNAi to protect the kidney from hypoxic injury by silencing the FAS death receptor and to investigate whether silencing FAS reduces inflammation or induces a nonspecific interferon (IFN) response. This proposal is supplementary to Project 2 of NIH grant (U19- AI56900) """"""""RNA interference as a weapon against bioterrorism"""""""". The parent program project investigates the interaction of viral infection with RNA interference (RNAi) and the development of strategies to deliver RNAi in vivo to treat bioterrorism agents. This proposal is a collaboration of the Principal Investigator at the CBR Institute at Harvard with Peter Hamar, a young investigator at Semmelweis University in Budapest, Hungary, exploiting the complementary strengths of Dr. Hamar in animal physiology studying mouse models of ischemia/reperfusion injury and shock and the experience and capability of the Lieberman laboratory in exploiting RNAi and assessing silencing using molecular, histochemical and immune based methods. Collaborative preliminary data, which form the basis of the current proposal, show impressive protection in mice from ischemia/reperfusion injury to the kidney by silencing FAS expression. The collaboration fostered by this grant will not only advance the development of therapeutic application of RNAi to an important clinical problem, but will also help the Principal Investigator's laboratory to become adept in mouse surgical methods and physiology and will provide the resources for Dr. Hamar to perform the proposed experiments and broaden his research capability to master molecular and immunology methods.
The specific aims of the FIRCA proposal are to (1) investigate the potential of modified siRNAs to silence FAS expression in the kidney when delivered by intravenous injection or local catheterization and provide protection from renal ischemia and (2) determine whether silencing FAS during renal ischemia modulates inflammatory and interferon responses in the kidney and systemically.
