The Role of KIBRA Signaling in Podocyte Injury

项目摘要：尽管肾小球足细胞被认为是蛋白尿肾损伤的靶细胞 在肾脏病的临床治疗中，细胞特异性治疗仍然缺乏。一个关键的障碍是对 疾病过程中足细胞损伤的机制。我们的初步数据已经确定Kibra(肾脑蛋白)是一种 足细胞损伤的潜在介体。Kibra在人类疾病中的表达增加，并且Kibra在 足细胞在体外和体内都具有保护作用。我们已经证明Kibra抑制了河马的信号 途径效应器是相关蛋白(YAP)，并破坏正常的肌动蛋白细胞骨架动力学。Kibra的表情是 在TGFBR1转基因小鼠和CD2AP基因敲除足细胞中也增加。我们的中心假设是转化生长因子- β/Smad信号导致足细胞Kibra表达上调，导致足细胞损伤。此外，作为一种疾病 相关地，我们假设Kibra的过度表达将足以诱发和促进肾小球疾病 进展，而Kibra缺失在慢性肾小球疾病模型中将具有保护作用。该计划的基本原理 建议的研究是，确定Kibra在肾小球疾病进展中的作用将增加对 足细胞损伤的机制和推进靶向治疗的探索。我们的假设将由三个人来检验 具体目标： 目标1将定义足细胞Kibra表达增加的上游调控。 目的2将确定Kibra在足细胞中的过度表达是否促进体内肾小球疾病的进展。 目的3将确定Kibra缺失是否能减少慢性肾小球疾病的足细胞损伤。 候选人和培训：此应用程序的主要目标是支持Kristin Meliambro博士的职业生涯 发展成为足细胞生物学和肾小球疾病领域的独立基础科学家。Dr。 Meliambro计划在四个领域开展培训活动：1)肾小球疾病、急性肾损伤的动物模型 (AKI)和慢性肾脏疾病(CKD)；2)足细胞生物学和细胞信号，重点是河马 信号途径；3)先进的成像技术；4)科学写作和演讲技能。 为了实现这一目标，她组建了一个由何慈江博士领导的指导和咨询团队，该团队由 肾脏学博士和柯克·坎贝尔博士，伊坎大学肾病学研究奖学金项目副教授兼主任 西奈山医学院。何博士和坎贝尔博士都是前K08奖获得者，加起来有四个 R01授予他们在足细胞生物学领域拥有专业知识的人。 环境：ISMMS在医学和科学培训、生物医学研究和患者方面处于国际领先地位 关心。研究是重中之重，因为ISMMS在美国国立卫生研究院资助的医学院中排名第13位，由美国新闻和 世界报告和美国医学院协会每名主要研究员的研究经费第二名 (AAMC)。ISMMS的肾病学部在研究方面处于国际领先地位，特别是在 足细胞生物学。

Project Summary: Despite the acceptance of the glomerular podocyte as the target cell for injury in proteinuric kidney disease, cell-specific therapy remains absent in clinical nephrology. A critical barrier is the limited understanding of the mechanisms of podocyte injury during disease. Our preliminary data has identified KIBRA (KIdney BRAin protein) as a potential mediator of podocyte injury. KIBRA's expression is increased in human disease, and silencing of KIBRA in podocytes is protective in vitro and in vivo. We have demonstrated that KIBRA inhibits the signaling of the Hippo pathway effector Yes-associated protein (YAP) and disrupts normal actin cytoskeletal dynamics. KIBRA expression was also increased in Tgfbr1 transgenic mice and in CD2AP knockdown podocytes. Our central hypothesis is that TGF- β/Smad signaling leads to upregulation of KIBRA in podocytes, resulting in podocyte injury. Additionally, as a disease correlate, we hypothesize that KIBRA overexpression will be sufficient to induce and promote glomerular disease progression, while KIBRA deletion in models of chronic glomerular disease will be protective. The rationale for the proposed research is that defining the role of KIBRA in glomerular disease progression will increase understanding of the mechanisms of podocyte injury and advance the quest for targeted therapeutics. Our hypothesis will be tested by three Specific Aims: Aim 1 will define the upstream regulation of increased KIBRA expression in podocytes. Aim 2 will determine whether KIBRA overexpression in podocytes promotes glomerular disease progression in vivo. Aim 3 will determine if KIBRA deletion reduces podocyte injury in chronic glomerular disease. Candidate and Training: The primary objective of this application is to support Dr. Kristin Meliambro's career development into an independent basic scientist in the fields of podocyte cell biology and glomerular diseases. Dr. Meliambro's proposed training activities are in four areas: 1) animal models of glomerular diseases, acute kidney injury (AKI), and chronic kidney disease (CKD); 2) podocyte cell biology and cell signaling, with a focus on the Hippo signaling pathway; 3) advanced imaging techniques; 4) scientific writing and oratory skills. To achieve this, she has assembled a mentoring and advisory team led by Dr. John Cijiang He, Chief of the Division of Nephrology, and Dr. Kirk Campbell, Associate Professor and Director of the Nephrology Fellowship Program at the Icahn School of Medicine at Mount Sinai (ISMMS). Both Drs. He and Campbell are former K08 awardees with combined four R01 grants between them who have expertise in the field of podocyte cell biology. Environment: The ISMMS is an international leader in medical and scientific training, biomedical research, and patient care. Research is a top priority, as ISMMS is ranked 13th among U.S. medical schools for NIH funding by US News and World Report and 2nd in research dollars per principal investigator by the Association of American Medical Colleges (AAMC). The Division of Nephrology at ISMMS is an international leader in research, particularly in the area of podocyte cell biology.