The Role of Autophagy in LPS-Induced Acute Kidney Injury

描述（由申请人提供）：该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博士在内科（芝加哥大学）完成了住院医师实习，在肾脏病学（西奈山医学院）获得了奖学金，并在过去几年中获得了基础科学研究经验。目前的申请旨在通过利用西奈山现有的智力和物质资源，将Leventhal博士从实习生转变为独立调查员。罗斯博士已经指导过几位成功的受训者，他将指导利文塔尔博士的整个培训过程。Ross博士是肾脏病部门的奖学金项目主任，是美国国立卫生研究院资助的独立研究者，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，美国国立卫生研究院资助的研究员，也是一位有成就的导师，他将担任联合导师。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，包括经常与他的导师会面，与他的咨询委员会会面，并在他的实习早期注册课程，以提高他在分子/细胞生物学信号转导，免疫学，科学伦理和拨款准备方面的知识基础。Leventhal博士将参加研讨会和国家会议，在那里他将展示他的研究，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推进对脓毒性急性肾损伤（AKI）发病机制的理解，这是一个常见的和毁灭性的临床问题。在这项申请中，他建议使用人肾小管上皮细胞（RTEC）系和一种新的小鼠模型来研究自噬如何影响脓毒性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降解。已知自噬影响许多人类疾病，但它是否调节脓毒性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LPS暴露的RTEC中诱导自噬的信号通路。在第三个目标中，他将确定注射LPS后，近端小管自噬的条件敲除是否会加重肾损伤。这将是第一个评估自噬如何调节脓毒性AKI的体内研究。西奈山肾脏病科为医师调查员提供了理想的培训环境，Leventhal博士将获得出色的指导，广泛的教育和强有力的制度支持，为他培养成功的医师调查员职业生涯提供了最好的机会。

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.