Metabolic and developmental regulation by AMPK in PRKAG2-associated cardiomyopathy

描述（由申请人提供）：本提案详细介绍了John T. Hinson博士心血管医学指导职业发展（K08）的全面五年培训计划。申请人是HHMI医学研究员项目的实习生，并通过ABIM加速研究途径在布莱根妇女医院和马萨诸塞州总医院完成了心血管医学和内科的临床培训。在该提案中，申请人概述了一个全面的研究培训计划，利用他之前在人类遗传学和代谢方面的培训，以及在构建多能干细胞疾病模型、基因组编辑、代谢组学和通量分析以及信号转导方面的新技能，以揭示AMPK-PRKAG2相关心肌病机制的新见解。Hinson博士将在Christine E. Seidman，医学博士，哈佛医学院和Brigham and Women's Hospital的Thomas W. Smith医学和遗传学教授的主要指导下，她既是一位杰出的临床心脏病专家，也是Howard Hughes医学研究所和美国国家科学院的成员。Seidman博士和她的丈夫Jonathan Seidman博士是世界知名的人类和分子遗传学家，专注于心血管遗传学。在过去的二十年里，塞德曼夫妇指导了无数年轻的研究人员，他们作为内科科学家走向了成功、独立的研究事业。Hinson博士的职业发展计划包括在哈佛医学院和布里格姆妇女医院的教育资源。除了拥有最先进的实验室环境中的资源外，他还聚集了一个咨询委员会，其中包括基因组编辑和下一代测序技术、线粒体生物学和信号转导方面的世界专家。申请人的主要目标是1)确定特异性PRKAG2突变如何导致糖原储存和左心室肥厚，2)阐明AMPK的代谢感知如何影响tgf - β信号通路，最后3)在其他心肌病小鼠模型中通过化学激活靶向AMPK。为此，Hinson博士将利用TALEN基因组编辑创建的PRKAG2-N488I心肌病的创新iPS模型，使用LC-MS结合标记底物的通量分析进行全球代谢评估，并研究连接AMPK代谢传感到AKT和tgf - β途径的信号转导途径。展望未来，Hinson博士将利用这一职业发展计划为成为一名独立的学术医师科学家奠定基础。

DESCRIPTION (provided by applicant): This proposal details a comprehensive five-year training program for mentored career development (K08) in cardiovascular medicine for Dr. John T. Hinson. The applicant is a prior trainee in the HHMI Medical Fellows program and has completed his clinical training in Cardiovascular Medicine at Brigham and Women's Hospital and Internal Medicine at Massachusetts General Hospital through the ABIM accelerated research pathway. In this proposal, the applicant has outlined a comprehensive research-training program that leverages his prior training in human genetics and metabolism with newly acquired skills in building pluripotent stem cell models of disease, genome editing, metabolomics and flux analysis, and signal transduction, in order to shed novel insight into the mechanisms of AMPK-PRKAG2 associated cardiomyopathy. Dr. Hinson will be under the primary mentorship of Christine E. Seidman, M.D, Thomas W. Smith Professor of Medicine and Genetics at Harvard Medical School and Brigham and Women's Hospital, who is both a distinguished clinical cardiologist and member of the Howard Hughes Medical Institute and National Academy of Sciences. Dr. Seidman and her husband Dr. Jonathan Seidman are world-renown human and molecular geneticists with a focus on cardiovascular genetics. Over the last twenty years, the Seidmans have mentored countless young investigators who go on to successful, independent research careers as physician scientists. Dr. Hinson's career development plan includes educational resources at Harvard Medical School and Brigham and Women's Hospital. In addition to the resources in Dr. Seidman's state-of -the-art laboratory environment, he has gathered an advisory committee that includes world experts in genome editing and next-generation sequencing technology, mitochondrial biology, and signal transduction. The applicant's primary goals are to 1) identify how specific PRKAG2 mutations cause glycogen storage and left ventricular hypertrophy, 2) elucidate how metabolic sensing by AMPK impacts the TGF-beta signaling pathway, and finally 3) target AMPK by chemical activation in other mouse models of cardiomyopathy. Towards this, Dr. Hinson will utilize an innovative iPS model of PRKAG2-N488I cardiomyopathy created with TALEN genome editing, perform a global metabolic assessment with LC-MS combined with flux analysis of labeled substrates, and study signal transduction pathways that connect metabolic sensing by AMPK to AKT and TGF-beta pathways. Going forward, Dr. Hinson will use this career development plan to build the foundation for a career as an independent, academic physician scientist.