Protein interactions underlying Fas-mediated DISC in Cholangiocarcinoma

描述(由申请人提供)：本提案的目标是将申请人以前在计算建模方面的研究专长与癌症研究相结合，并帮助申请人获得所需的额外技能，以利用多学科方法指导独立的生物医学研究实验室研究癌症发病机制和开发癌症化疗。申请者将由杰伊·M·麦克唐纳博士指导，他是研究钙调蛋白(CaM)在包括癌症发病机制在内的许多疾病中作为信号转导的作用的专家。培训计划包括教学课程、实验实验室培训、研讨会和期刊俱乐部以及与导师和咨询委员会的定期会议的适当结合。指导培训对于申请者完成拟议的计算和生物实验方法在癌症发病机制方面的研究至关重要，并为候选人在未来生物医学领域的独立NIH资金申请中具有竞争力做好准备。胆管癌是一种致命的癌症，在过去的几十年里，它的发病率在全球范围内一直在上升。调控Fas介导的细胞凋亡是一种很有前途的预防肿瘤进展的方法。本应用的目的是通过从结构和功能的角度研究Fas介导的死亡诱导信号复合体(DISC)形成的蛋白质相互作用，了解Fas介导的信号通路在胆管癌发病机制中的作用。假说是CaM和Fas之间的直接相互作用通过调节视盘的形成来调节细胞凋亡，并代表了癌症化疗药物的潜在位置。这一假设将通过追求两个具体目标来检验。每个目标都将使用生物物理模拟和生物化学实验。具体目的1.确定CaM/Fas结合在胆管癌细胞Fas介导的信号通路中的作用。具体目的2.确定钙调素拮抗剂影响胆管癌细胞Fas介导的视盘形成的分子机制。

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.