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

基本信息

批准号：
9182902
负责人：
John Travis Hinson
金额：
$ 17.71万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
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/9182902
关键词：
5&apos -AMP-activated protein kinase Advisory Committees Affect Agonist Alleles 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 Disease model Engineering Environment Fatty Acids Fibrosis Foundations Functional disorder Gene Mutation General Hospitals Genes Genetic Genetic Transcription Genus Hippocampus Glucose Glycogen Goals 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 public health relevance response sensor skills sudden cardiac death transcription activator-like effector nucleases transcriptome sequencing

项目摘要

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（由应用程序提供）：该提案详细介绍了一项针对John T. Hinson博士心血管医学的指导职业发展五年培训计划（K08）。该申请人是HHMI医疗研究员计划的先前学员，并通过ABIM加速研究途径在Brigham和Massachusetts General Hospital的Brigham以及妇女医院和内科医学进行了心血管医学培训。在这项建议中，适用的概述了一项全面的研究培训计划，该计划利用他在人类遗传学和代谢方面的先前培训，并通过新获得的技能在构建多能疾病的干细胞模型，基因组编辑，代谢组学和磁通分析和信号翻译方面，以使Ampk-Promkag 2相关的机制为机制提供新颖的机制。 Hinson博士将在哈佛医学院的托马斯·W·史密斯医学和遗传学教授以及布里格姆和妇女医院的克里斯汀·E·塞德曼（Christine E. 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，重点是心血管遗传学。在过去的二十年中，Seidmans指导了无数的年轻调查员，他们继续从事物理科学家的成功，独立的研究职业。 Hinson博士的职业发展计划包括哈佛医学院，杨百翰和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，其中包括世界上的世界专家和下一代测序技术，线粒体生物学和信号转导。申请人的主要目标是1）确定特定的PRKAG2突变如何引起糖原储存和左心室肥大，2）阐明AMPK的代谢感应如何影响TGF-BETA信号传导途径，最后3）三）靶向AMPK通过化学型心肌病小鼠模型中的化学激活。为此，Hinson博士将利用由Talen Genome编辑创建的PRKAG2-N488I心肌病的创新IPS模型，并通过LC-MS进行全球代谢评估，并结合标记底物的通量分析，并研究信号传递途径，并通过AMPK与Akt和Tgf-Betawore的代谢敏感性连接代谢敏感性。展望未来，Hinson博士将利用这项职业发展计划为作为独立的学术医师科学家的职业建立基础。