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

描述(由申请人提供)：本提案详细介绍了为期5年的导师奖的研究和培训计划，旨在促进首席研究员作为波士顿大学医学院新任命的初级教员、内科医生和科学家的职业发展。这一奖项将使用新的模型和方法扩展研究人员以前的研究。研究人员的直接职业目标是探索通过AMPK-LKB1的能量信号、心脏代谢和糖尿病心力衰竭的心肌细胞生物学。首席研究员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，以及耶鲁大学医学院的博士学位。威尔逊·科鲁奇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内科的首席研究员，他在那里担任医学教授、心血管内科主任和心肌生物学部门的主任。导师和该机构拥有初级教师科学成就和成功职业发展的良好记录，并建立了心肌细胞生物学、细胞信号、蛋白质组学、糖尿病和心力衰竭等多学科项目。该奖项中概述的培训计划包括授课讲座、一对一和小组指导，以及参加心脏代谢研究的国家/国际会议。首席研究人员渴望利用获得的培训、专业知识和科学数据在该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2型糖尿病小鼠模型中作为能量信号协调者在心脏中的作用，并探索AMPK通过上游AMPK激酶(AMPKK)LKB1的调节和药物激活。这项建议的第一个目的是调查固有的AMPK激活是否在糖尿病心力衰竭的发生和发展中被错乱地激活。一个关键的结果将是研究糖尿病心脏中固有的AMPK活性是否减少，以及AMPK缺乏是否会加剧糖尿病心脏病。第二个目的是检测LKB1翻译后修饰对糖尿病心脏中LKB1-AMPK信号的影响，并使用LKB1缺失的心脏来测试LKB1对糖尿病心脏AMPK激活的贡献。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，特别是在响应工作负荷的急性变化时，评估了活性氧生成和线粒体功能的变化。总而言之，这项建议调查了糖尿病心脏中的一个重要信号通路，同时允许研究人员获得培训和专业知识，从而成功地成为一名独立的内科科学家。 公共卫生相关性：这项建议使用小鼠模型来研究糖尿病期间心脏关键代谢途径的激活和调节，糖尿病是人类常见的临床疾病。这项资助中研究的中心通路(AMPK和LKB1)是许多糖尿病治疗的靶点，因此了解它们的调节可能会导致糖尿病心脏病的治疗进展。

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. PUBLIC HEALTH RELEVANCE: This proposal uses mouse models to study the activation and regulation of key metabolic pathways in the heart during diabetes mellitus, which is a common human clinical condition. The central pathways studied in this grant (AMPK and LKB1) are targeted by many therapies for diabetes mellitus, and therefore understanding their regulation could lead to therapeutic advances for diabetic heart disease.