The role and regulation of the LKB1-AMPK axis in diabetic cardiomyopathy

描述（由申请人提供）：本提案详细说明了为期5年的指导奖的研究和培训计划，旨在促进主要研究者作为波士顿大学医学院新任命的初级教员医生-科学家的职业发展。该奖项将使用新的模型和方法扩展研究人员以前的研究。研究者的直接职业目标是探索糖尿病心力衰竭中通过AMPK-LKB 1，心脏代谢和心肌细胞生物学的能量信号。主要研究者的教育背景包括临床心脏病学培训、心脏病学博士后研究奖学金和博士学位。在耶鲁大学医学院。Wilson Colucci博士是心肌细胞生物学和心力衰竭方面的专家，他将指导波士顿大学医学院心血管医学科的主要研究者，他是医学教授，心血管医学主任和心肌生物学单元主任。导师和该机构有很强的科学成就和初级教师成功的职业发展记录，在心肌细胞生物学，细胞信号传导，蛋白质组学，糖尿病和心力衰竭方面建立了多学科计划。该奖项中概述的培训计划包括教学讲座，一对一和小组指导，以及参加国家/国际心脏代谢研究会议。主要研究者希望利用获得的培训，专业知识和科学数据，在本奖项结束时申请独立研究资金。 该提案的总体目标是了解AMPK在心脏中作为2型糖尿病小鼠模型中能量信号的协调者的作用，并探索AMPK通过上游AMPK激酶（AMPKK）LKB 1的调节和药理学激活。本研究的第一个目的是研究内源性AMPK激活是否在糖尿病心力衰竭的发展和进展中紊乱。一个关键的结果将是研究糖尿病心脏中内源性AMPK激活是否减少，以及AMPK缺乏是否会加重糖尿病心脏病。第二个目的是检查LKB 1翻译后修饰对糖尿病心脏中LKB 1-AMPK信号传导的影响，并使用LKB 1缺陷的心脏测试LKB 1对糖尿病心脏中AMPK活化的贡献。第三个目的是评估外源性AMPK激活是否改善了糖尿病心脏的功能和代谢表型，特别是对工作负荷的急性变化的反应，评估活性氧生成和线粒体功能的变化。总之，该提案调查了糖尿病心脏中的一个重要信号通路，同时允许研究人员接受培训和专业知识，成功地成为一名独立的医生-科学家。

DESCRIPTION (provided by applicant): This proposal details the research and training plan for a 5-year mentored award designed to facilitate the principal investigator's career development as a newly appointed junior faculty member physician-scientist at the Boston University School of Medicine. This award will expand the investigator's previous research using new models and methods. The immediate career goal of the investigator is to explore energetic signaling via AMPK-LKB1, cardiac metabolism, and cardiomyocyte biology in diabetic heart failure. The principal investigator's educational background includes clinical cardiology training, a post-doctoral research fellowship in cardiology, and Ph.D. at the Yale University School of Medicine. Dr. Wilson Colucci, an expert in cardiomyocyte biology and heart failure, will mentor the principal investigator in the section of Cardiovascular Medicine at Boston University School of Medicine where he is Professor of Medicine, Chief of Cardiovascular Medicine, and the Director of the Myocardial Biology Unit. The mentor and the institution have strong tract records of scientific accomplishment and successful career development of junior faculty, with established multi-disciplinary programs in cardiomyocyte biology, cellular signaling, proteomics, diabetes, and heart failure. The training plan outlined in this award includes didactic lectures, one-on-one and group mentoring, and attendance at national/international meetings in cardio-metabolic research. The principal investigator aspires to utilize the acquired training, expertise, and scientific data to apply for independent research funding at the conclusion of this award. The overall goal of this proposal is to understand the role of AMPK in the heart as a coordinator of energetic signaling in murine models of type 2 diabetes and to explore regulation and pharmacologic activation of AMPK via the upstream AMPK kinase (AMPKK), LKB1. The first aim of this proposal is to investigate whether intrinsic AMPK activation is deranged in the development and progression of diabetic heart failure. A key outcome will be to investigate whether intrinsic AMPK activation is decreased in the diabetic heart and whether AMPK deficiency exacerbates diabetic heart disease. The second aim is to examine the impact of LKB1 post- translational modifications on LKB1-AMPK signaling in the diabetic heart, and test the contribution of LKB1 to AMPK activation in the diabetic heart using hearts deficient in LKB1. The third aim is to assess whether extrinsic AMPK activation is improves the functional and metabolic phenotype of the diabetic heart, particularly in response to acute changes in workload, evaluating changes in reactive oxygen species generation and mitochondrial function. In summary, this proposal investigates an important signaling pathway in the diabetic heart while allowing the investigator to acrue the training and expertise to successfully become an independent physician-scientist.