Protein interactions underlying Fas-mediated DISC in Cholangiocarcinoma

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DESCRIPTION (provided by applicant): The goal of this proposal to align the applicant's previous research expertise in computational modeling with cancer research, and help the applicant to acquire additional skills needed to direct an independent biomedical research laboratory utilizing a multidisciplinary approach to study cancer pathogenesis and develop cancer chemotherapy. The applicant will be mentored by Dr. Jay M. McDonald, an expert in the study of the role of calmodulin (CaM) as a signal transducer in many diseases including cancer pathogenesis. The training plan includes the proper combination of didactic coursework, experimental laboratory training, seminars and journal clubs and regular meetings with the mentor and Advisory Committee. The mentored training is essential for the applicant to accomplish the proposed research in cancer pathogenesis with combined computational and biological experimental approaches, and prepare the candidate to be competitive for future independent NIH funding applications in biomedicine. Cholangiocarcinoma is a fatal cancer and its rates have been rising worldwide over the past several decades. Regulation of Fas-mediated apoptosis is a promising approach to prevent cancer progression. The goal of this application is to understand Fas-mediated signaling pathways in the pathogenesis of cholangiocarcinoma by focusing on protein interactions underlying Fas-mediated death inducing signaling complex (DISC) formation from both structural and functional point of views. The hypothesis is that the direct interaction between CaM and Fas modulates apoptosis by regulating the formation of the DISC and represents a potential site for cancer chemotherapeutics. The hypothesis will be tested by pursuing two specific aims. Each aim will employ both biophysical simulations and biochemical experiments. Specific Aim 1. Determine the role of CaM/Fas binding in regulating Fas-mediated signaling pathways in cholangiocarcinoma cells. Specific Aim 2. Determine the molecular mechanisms of the effect of CaM antagonists on Fas- mediated DISC formation in cholangiocarcinoma cells.