Metabolic and developmental regulation by AMPK in PRKAG2-associated cardiomyopathy

描述（由申请人提供）：本提案详细介绍了一个全面的五年培训计划，指导职业发展（K 08）在心血管医学博士约翰T。Hinson申请人是HHMI医学研究员计划的前实习生，并通过ABIM加速研究途径完成了布里格姆妇女医院心血管医学和马萨诸塞州总医院内科的临床培训。在该提案中，申请人概述了一项全面的研究培训计划，该计划利用他先前在人类遗传学和代谢方面的培训，以及在构建疾病的多能干细胞模型、基因组编辑、代谢组学和通量分析以及信号转导方面新获得的技能，以便对AMPK-PRKAG 2相关心肌病的机制进行新的见解。希森博士将在克莉丝汀E的主要指导下。Seidman，M.D，托马斯W.他是哈佛医学院和布里格姆妇女医院的医学和遗传学史密斯教授，他既是杰出的临床心脏病专家，也是霍华德休斯医学研究所和国家科学院的成员。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20年里，塞德曼夫妇指导了无数年轻的研究人员，他们作为医生科学家成功地从事独立的研究事业。Hinson博士的职业发展计划包括哈佛医学院和布里格姆妇女医院的教育资源。除了Seidman博士最先进的实验室环境中的资源外，他还召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）鉴定特定PRKAG 2突变如何引起糖原蓄积和左心室肥大，2）阐明AMPK的代谢传感如何影响TGF-β信号传导途径，以及最后3）在其他心肌病小鼠模型中通过化学活化靶向AMPK。为此，Hinson博士将利用TALEN基因组编辑创建的PRKAG 2-N488 I心肌病的创新iPS模型，结合LC-MS和标记底物的通量分析进行全球代谢评估，并研究将AMPK的代谢传感与AKT和TGF-β途径连接起来的信号转导途径。展望未来，Hinson博士将利用这一职业发展计划为作为一名独立的学术医生科学家的职业生涯奠定基础。

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.