HARNESSING THE LYSOSOME MACHINERY IN MACROPHAGES TO PREVENT HEART FAILURE

项目摘要 该职业发展建议旨在将主要研究者（PI）培训为 独立的物理学家和科学家PI具有先前的基础和转化研究经验，包括分子生物学博士学位 遗传学和细胞生物学（Stephen J. Kron博士）和脂蛋白代谢和巨噬细胞 胆固醇流出（丹尼尔J.雷德博士），在每个训练阶段的第一作者出版物中达到顶峰。现有 巨噬细胞胆固醇代谢中PI的研究激发了对巨噬细胞在心脏中的基本作用的兴趣。 心肌梗死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专家， 接受过内科（马萨诸塞州总医院）、心血管疾病和 高级心力衰竭和心脏移植奖学金（均来自宾夕法尼亚大学，Kenneth B博士）。 Margulies）。PI之前的临床和研究经验促使他制定了这5年的职业生涯 发展计划，提供正式的培训，巨噬细胞免疫学和进一步的实验室培训， 损伤和心力衰竭动物模型。研究建议的主要假设是， 巨噬细胞溶酶体机制将防止由于心肌梗塞引起的心力衰竭。PI的初步研究 表明巨噬细胞特异性转录因子EB（TFEB）过表达，TFEB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心肌重构。PI将对此进行研究 通过详细的心脏表型和心肌功能评估， 雄性和雌性小鼠（目标1），心肌炎症反应的详细分析（目标2），以及 TFEB可改善巨噬细胞存活和增强抗炎作用的基本亚细胞机制 （目标3）。目标的完成将为PI提供必要的培训，以实现科学独立性， 包括心脏损伤模型（目标1）和巨噬细胞免疫学（目标2和3）的进一步培训。阿比纳夫博士 Diwan是心力衰竭中溶酶体生物学建模的专家，将担任主要导师，而Gwendalyn博士 兰多夫，在巨噬细胞免疫学的领先专家，将担任共同导师。PI将从中受益 导师团队和华盛顿大学提供的大量基础和翻译资源，是首屈一指的 这是一个学术机构，非常坚定地致力于培养医生-科学家。此外，在 在这个奖项的过程中，PI将完成免疫学研究生课程，前往科学会议，并从 一个由迪万博士和兰多夫博士以及道格拉斯曼博士组成的职业咨询委员会的投入， 公认的心力衰竭专家StuartKornfeld博士是一位溶酶体生物学家，他培养了100多名研究生， 以及国际知名的免疫学专家Marco科隆纳博士。本申请 实现PI的直接培训目标，以获得心力衰竭免疫生物学方面的专业知识， 长期目标是成为一名专注于心血管疾病研究的独立医生科学家。

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.