The Role of Autophagy in LPS-Induced Acute Kidney Injury

描述(由申请人提供)：本建议书描述了一个全面的5年培训计划，旨在促进学术医学事业的持续发展。莱文塔尔博士已完成内科住院医师资格(大学西奈山医学院)，并在过去的几年里积累了基础科学研究经验。目前的应用程序旨在通过利用Mt.公司现有的智力和物质资源，将莱文塔尔博士从受训人员转变为独立调查员。西奈半岛。罗斯博士已经指导了几名成功的实习生，他将在整个培训过程中指导莱文塔尔博士。罗斯博士是肾脏病学部奖学金计划主任，是由美国国立卫生研究院资助的知名独立研究员，也是艾滋病毒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，也是美国国立卫生研究院资助的研究人员，他本身也是一位成就斐然的导师，他将担任联合导师。一个由备受尊敬和成功的首席调查人员组成的咨询委员会将就科学和职业问题提供额外的咨询。莱文塔尔博士的职业发展计划是全面的，包括经常与他的导师会面，与他的顾问委员会会面，并在他实习的早期报名参加课程，以提高他在分子/细胞生物学信号转导、免疫学、科学伦理学和拨款准备方面的知识基础。莱文塔尔博士将参加研讨会和国家会议，在那里他将介绍他的研究，建立合作关系，并了解他所在领域的最新进展。莱文塔尔博士的研究利用最先进的分子方法来促进对败血症急性肾损伤(AKI)发病机制的了解，AKI是一种常见的破坏性临床问题。在这项应用中，他建议使用人肾小管上皮细胞系(RTEC)和一种新的小鼠模型来研究自噬如何影响败血症AKI的发病机制。自噬是一种细胞内过程，导致隔离的细胞质成分的降解。已知自噬影响许多人类疾病，但它是否调节败血症AKI尚不清楚。在第一个具体目标中，他将确定抑制自噬基因表达和药物自噬抑制如何影响脂多糖暴露后RTEC的损伤。在第二个特定目标中，将使用通路特异性抑制物和蛋白质分析来确定导致内毒素暴露的RTEC自噬诱导的信号通路。在第三个目标中，他将确定有条件地敲除近端小管中的自噬是否会加剧注射脂多糖后的肾脏损伤。这将是第一次评估自噬如何调节败血症AKI的体内研究。西奈山肾病分部是内科研究人员的理想培训环境，莱文塔尔博士将在那里获得出色的指导、广泛的教育和强有力的机构支持，为他提供作为一名内科研究人员培养成功职业生涯的最佳机会。

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.