Metabolic and developmental regulation by AMPK in PRKAG2-associated cardiomyopathy

 描述(由申请人提供)：这份建议书详细说明了约翰·T·辛森博士在心血管医学方面的指导职业发展(K08)的综合五年培训计划。申请人是HHMI医学研究员计划的优先实习生，并通过ABIM加速研究途径完成了他在布里格姆妇女医院的心血管内科和马萨诸塞州综合医院的内科的临床培训。在这份提案中，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新陈代谢方面的培训，以及在建立疾病的多潜能干细胞模型、基因组编辑、代谢组学和通量分析以及信号转导方面的新技能，以期对AMPK-PRKAG2相关心肌病的机制有新的见解。欣森博士将在哈佛医学院和布里格姆妇女医院的医学和遗传学教授克里斯汀·E·塞德曼医学博士和托马斯·W·史密斯教授的主要指导下工作。塞德曼博士是一位杰出的临床心脏病专家，也是霍华德·休斯医学研究所和美国国家科学院的成员。塞德曼博士和她的丈夫乔纳森·塞德曼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继续着成功的、独立的研究生涯。辛森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。除了塞德曼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)确定特定的PRKAG2突变如何导致糖原储存和左室肥厚，2)阐明AMPK的代谢感应如何影响转化生长因子-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来靶向AMPK。为此，Hinson博士将利用利用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，并研究将AMPK的代谢感应连接到AKT和转化生长因子-β途径的信号转导途径。展望未来，辛森博士将利用这一职业发展计划，为成为一名独立的、学术性质的内科科学家奠定基础。

 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.