The Role of Autophagy in LPS-Induced Acute Kidney Injury

描述（由申请人提供）：本提案描述了一个全面的5年培训计划，旨在促进学术医学事业的持续发展。Leventhal博士已完成内科住院医师（芝加哥大学），肾脏病学奖学金（西奈山医学院），并在过去几年中获得了基础科学研究经验。目前的应用程序的结构是过渡博士Leventhal从实习生到独立调查员，利用智力和物质资源，在山。西奈 罗斯博士已经指导过几位成功的学员，他将在整个培训过程中指导利文塔尔博士。Ross博士是肾脏科的奖学金项目主任，是NIH资助的独立研究者，也是HIV相关肾脏疾病领域公认的领导者。岳博士是自噬领域的专家，NIH资助的研究人员，也是一位有成就的导师，他将担任共同导师。一个由备受尊敬和成功的主要研究人员组成的咨询委员会将在科学和职业问题上提供额外的咨询。Leventhal博士的职业发展计划是全面的，包括与他的导师经常会面，与他的咨询委员会会面，并在他的培训早期报名参加课程，以提高他的分子/细胞生物学信号转导，免疫学，科学伦理学和拨款准备的知识基础。Leventhal博士将参加研讨会和全国会议，在那里他将介绍他的研究，建立合作，并了解他的领域的最新进展。 Leventhal博士的研究利用最先进的分子方法来促进对脓毒性急性肾损伤（阿基）发病机制的理解，这是一种常见的破坏性临床问题。在这项应用中，他提出使用人肾小管上皮细胞（RTEC）系和新型小鼠模型研究自噬如何影响脓毒性阿基的发病机制。自噬是一种细胞内过程，导致被隔离的细胞质元件降解。已知自噬影响许多人类疾病，但它是否调节脓毒性阿基尚不清楚。在第一个具体目标中，他将确定自噬基因表达的抑制和药理学自噬抑制如何影响LPS暴露后的RTEC损伤。在第二个具体目标中，将使用途径特异性抑制剂和蛋白质分析来确定负责LPS暴露的RTEC中自噬诱导的信号传导途径。在第三个目标中，他将确定近端小管自噬的条件性敲除是否会导致LPS注射后的肾损伤。这些将是第一个评估自噬如何调节脓毒性阿基的体内研究。 西奈山肾脏科是医生研究者的理想培训环境，Leventhal博士将获得出色的指导，广泛的教育和强大的机构支持，为他提供最好的机会，培养一个成功的职业生涯作为一名医生研究者。

DESCRIPTION (provided by applicant): This proposal describes a comprehensive 5-year training program designed to foster the continued development of a career in academic medicine. Dr. Leventhal has completed residency in Internal Medicine (Univ. of Chicago), Fellowship in Nephrology (Mount Sinai School of Medicine), and spent the last years gaining basic science research experience. The current application is structured to transition Dr. Leventhal from trainee to independent investigator by leveraging intellectual and material resources available at Mt. Sinai. Dr. Ross, who has already mentored several successful trainees, will guide Dr. Leventhal throughout his training. Dr. Ross is the Fellowship Program Director for the Division of Nephrology, an established NIH-funded independent investigator and a recognized leader in the field of HIV-associated renal disease. Dr. Yue, an expert in the field of autophagy, an NIH-funded investigator, and an accomplished mentor in his own right, will serve as co-mentor. An advisory committee composed of highly regarded and successful principal investigators will provide additional counsel on both scientific and career issues. Dr. Leventhal's career development plan is comprehensive, including frequent meetings with his mentor, meetings with his advisory committee and enrolling in classes early in his traineeship to improve his knowledge base of molecular/cell biology signal transduction, immunology, scientific ethics, and grant preparation. Dr. Leventhal will attend seminars and national conferences where he will present his research, establish collaborations, and learn of recent advances in his field. Dr. Leventhal's research utilizes state-of-the-art molecular methods to advance understanding of the pathogenesis of septic acute kidney injury (AKI), a common and devastating clinical problem. In this application, he proposes to study how autophagy affects the pathogenesis of septic AKI using a human renal tubular epithelial cell (RTEC) line and a novel murine model. Autophagy is an intracellular process that results in the degradation of sequestered cytoplasmic elements. Autophagy is known to impact many human diseases but whether it modulates septic AKI is unknown. In the first specific aim, he will determine how suppression of autophagy gene expression and pharmacological autophagy inhibition affect RTEC injury after LPS exposure. In the second specific aim, the signaling pathways responsible for autophagy induction in LPS exposed RTEC will be determined using pathway specific inhibitors and protein analysis. In the third aim, he will determine whether conditional knockout of autophagy in the proximal tubule worsens renal injury following LPS injection. These will be the first in vivo studies to evaluate how autophagy modulates septic AKI. The Mount Sinai Division of Nephrology is an ideal training environment for physician investigators where Dr. Leventhal will receive outstanding mentoring, extensive education, and strong institutional support, providing him with the best possible opportunity to cultivate a successful career as a physician investigator.