Metabolic and developmental regulation by AMPK in PRKAG2-associated cardiomyopathy

PRKAG2 相关心肌病中 AMPK 的代谢和发育调节

• 批准号: 9264223
• 负责人: John Travis Hinson
• 金额: $ 11.52万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264223
• 关键词: 5' -AMP-activated protein kinase; Accounting; Advisory Committees; Affect; Agonist; Arrhythmia; Attenuated; Biogenesis; Biology; Bypass; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cell Respiration; Cell Size; Cell model; Cells; Chemicals; Chronic Kidney Failure; Clinical; Contractile Proteins; Data; Development; Development Plans; Dilated Cardiomyopathy; Disease; Engineering; Environment; Fatty Acids; Fibrosis; Foundations; Functional disorder; Gene Mutation; General Hospitals; Genes; Genetic; Genetic Medicine; Genetic Transcription; Genus Hippocampus; Glucose; Glycogen; Goals; Health; Heart; Heart Diseases; Histopathology; Homeostasis; Hospitals; Human; Human Genetics; Husband; Hypertrophic Cardiomyopathy; Hypertrophy; In Vitro; Inherited; Institutes; Insulin; Internal Medicine; Label; Laboratories; Left Ventricular Hypertrophy; Link; Massachusetts; Medical; Medicine; Mentors; Mentorship; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Mutation; Non-Insulin-Dependent Diabetes Mellitus; PI3K/AKT; PRKAG2 gene; Pathway interactions; Patients; Physicians; Pluripotent Stem Cells; Process; Protein Precursors; Proto-Oncogene Proteins c-akt; Regulation; Research; Research Personnel; Research Training; Resources; Risk; Role; Scientist; Series; Signal Transduction; Signal Transduction Pathway; Stem cells; Structure; Symptoms; TGF Beta Signaling Pathway; Technology; Testing; Training; Training Programs; Transforming Growth Factor beta; United States National Academy of Sciences; Ventricular; Wolff-Parkinson-White Syndrome; Woman; base; cardiogenesis; career; career development; cell growth; disease-causing mutation; effective therapy; fatty acid metabolism; fetal; genome editing; genome wide association study; glucose metabolism; human stem cells; in vivo; induced pluripotent stem cell; innovation; insight; medical schools; member; metabolomics; mortality; mouse model; mutant; new therapeutic target; next generation sequencing; novel; professor; programs; response; sensor; skills; sudden cardiac death; transcription activator-like effector nucleases; transcriptome sequencing

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.

描述（由申请人提供）：该提案详细介绍了 John T. Hinson 博士心血管医学领域指导职业发展 (K08) 的全面五年培训计划。申请人是 HHMI 医学研究员计划的先前实习生，并通过 ABIM 加速研究途径完成了布莱根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。在本提案中，申请人概述了一项综合研究培训计划，该计划利用他之前在人类遗传学和新陈代谢方面的培训以及新获得的建立疾病多能干细胞模型、基因组编辑、代谢组学和通量分析以及信号转导的技能，以便对 AMPK-PRKAG2 相关心肌病的机制提供新的见解。 Hinson 博士将接受哈佛医学院和布莱根妇女医院 Thomas W. Smith 医学和遗传学教授、医学博士 Christine E. Seidman 的主要指导，她是一位杰出的临床心脏病学家，也是霍华德休斯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 博士是世界著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，他们后来作为医学科学家取得了成功的独立研究生涯。 Hinson 博士的职业发展计划包括哈佛医学院和布莱根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领域的世界专家。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心室肥大，2) 阐明 AMPK 的代谢传感如何影响 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来靶向 AMPK。为此，Hinson 博士将利用通过 TALEN 基因组编辑创建的 PRKAG2-N488I 心肌病的创新 iPS 模型，利用 LC-MS 结合标记底物通量分析进行全局代谢评估，并研究将 AMPK 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，辛森博士将利用这一职业发展计划为作为一名独立的学术医师科学家的职业生涯奠定基础。