HARNESSING THE LYSOSOME MACHINERY IN MACROPHAGES TO PREVENT HEART FAILURE

项目总结 这份职业发展提案是为将首席调查员(PI)培训为 独立的医生兼科学家。具有基础和翻译研究经验，包括分子方面的博士学位 遗传学和细胞生物学(斯蒂芬·J·克伦博士)和脂蛋白代谢和巨噬细胞的博士后研究 胆固醇外流(丹尼尔J.雷德博士)，在培训的每个阶段的第一作者出版物中达到顶峰。前一部 巨噬细胞胆固醇代谢中PI的研究激发了人们对巨噬细胞在心脏中的基础作用的兴趣 因心肌梗死而失败，这是一个主要的公共卫生问题。PI是一名心力衰竭移植心脏病学家 曾接受内科(麻省总医院)、心血管疾病和 进展性心力衰竭和心脏移植奖学金(均为宾夕法尼亚大学的Kenneth B. 马古利斯)。PI以前的临床和研究经验促使了这5年职业生涯的形成 制定计划，提供巨噬细胞免疫学的正式培训和冠状动脉的进一步实验室培训 损伤和心力衰竭的动物模型。研究提案的主要假设是，增加 巨噬细胞溶酶体机制将预防心肌梗死所致的心力衰竭。来自猪场的初步研究 提示巨噬细胞特异性转录因子EB(TFEB)的过度表达是自噬的主要调节因子。 溶酶体途径，防止实验性心肌梗死后的心肌重塑。私家侦探将探索这一点 通过详细的心脏表型和心肌功能评估，提出假设并确认初步结果。 雄性和雌性小鼠(目标1)，详细分析心肌炎性反应(目标2)，并调查 TFEB改善巨噬细胞存活和增强抗炎作用的基本亚细胞机制 答复(目标3)。这些目标的完成将为PI提供必要的培训，以实现科学独立， 包括心脏损伤模型的进一步培训(目标1)和巨噬细胞免疫学(目标2和3)。阿比纳夫医生 Diwan是心力衰竭的溶酶体生物学建模专家，他将担任主要导师，而Gwendalyn博士将担任 巨噬细胞免疫学方面的领先专家兰道夫将担任共同导师。私家侦探将从中受益 指导团队和华盛顿大学提供的大量基础和翻译资源，是一位 学术机构，非常坚定地致力于培养内科科学家。此外，在 在这一奖项的课程中，PI将完成免疫学研究生课程，参加科学会议，并受益于 由Diwan博士和Randolph博士以及Douglas Mann博士组成的职业咨询委员会的投入 公认的心力衰竭专家斯图尔特·科恩菲尔德博士，一位溶酶体生物学家，培养了100多名研究生 和博士后研究员，以及享誉国际的免疫学专家马尔科·科隆纳博士。此应用程序 完成私人助理的即时培训目标，以获取心力衰竭的免疫生物学方面的专门知识，以及 长期目标是成为一名专注于心血管疾病研究的独立内科科学家。

Project summary This career development proposal has been engineered for the training of the principle investigator (PI) into an independent physician-scientist. The PI has prior basic and translational research experience including a PhD in molecular genetics and cell biology (Dr. Stephen J. Kron) and postdoctoral fellowship in lipoprotein metabolism and macrophage cholesterol efflux (Dr. Daniel J. Rader), culminating in first-author publications at each phase of training. The prior studies of the PI in macrophage cholesterol metabolism have motivated interests in the basic role of macrophages in heart failure due to myocardial infarction, a major public health problem. The PI is a heart failure transplant cardiologist and Clinical Instructor who trained in Internal Medicine (Massachusetts General Hospital), Cardiovascular Diseases, and Advanced Heart Failure and Cardiac Transplantation fellowship (both at University of Pennsylvania, Dr. Kenneth B. Margulies). Both prior clinical and research experiences of the PI motivated the formulation of this 5-year career development program to provide formal training in macrophage immunology and further laboratory training in coronary injury and animal models of heart failure. The main hypothesis of the research proposal is that augmenting the macrophage lysosomal machinery will prevent heart failure due to myocardial infarction. Preliminary studies from the PI indicate that macrophage-specific overexpression of transcription factor EB (TFEB), a master regulator of the autophagy- lysosome pathway, prevents myocardial remodeling after experimental myocardial infarction. The PI will explore this hypothesis and confirm the preliminary results by detailed cardiac phenotyping and assessment of myocardial function in male and female mice (Aim 1), detailed analysis of the myocardial inflammatory response (Aim 2), and investigation into basic subcellular mechanisms by which TFEB may improve macrophage survival and augment anti-inflammatory responses (Aim 3). Completion of the aims will provide the PI necessary training to achieve scientific independence, including further training in cardiac injury models (Aim 1), and macrophage immunology (Aims 2 and 3). Dr. Abhinav Diwan, an expert in modeling lysosome biology in heart failure, will serve as the primary mentor, while Dr. Gwendalyn Randolph, a leading expert in macrophage immunology, will serve as the co-mentor. The PI will benefit from this mentorship team and the tremendous basic and translational resources available at Washington University, a premier academic institution, with an exceptionally strong commitment to training physician-scientists. In addition, during the course of this award, the PI will complete graduate courses in immunology, travel to scientific meetings, and benefit from the input of a career advisory committee composed of the Drs. Diwan and Randolph, as well as Dr. Douglas Mann, a recognized expert in heart failure, Dr. Stuart Kornfeld, a lysosome biologist who has trained over 100 graduate student and postdoctoral fellows, and Dr. Marco Colonna, an internationally-regarded expert in immunology. This application fulfills the immediate training objectives of the PI to acquire expertise in the immuno-biology of heart failure, and the long-term goal of becoming an independent physician-scientist focused on cardiovascular disease research.