The Role of KIBRA Signaling in Podocyte Injury

KIBRA 信号传导在足细胞损伤中的作用

基本信息

批准号：
10408806
负责人：
Kristin Meliambro
金额：
$ 16.28万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408806
关键词：
Actins Acute Acute Renal Failure with Renal Papillary Necrosis Advisory Committees Animal Model Architecture Area Association of American Medical Colleges Basement membrane Biomedical Research Brain CD2-associated protein Cell Line Cells Cellular biology Chronic Chronic Kidney Failure Clinical Cytoskeleton Data Development Diabetic Nephropathy Disease Disease Progression Disease model Doxycycline Environment Family Fellowship Program Focal Adhesions Focal Segmental Glomerulosclerosis Foot Process Foundations Funding Gene Deletion Gene Expression Gene Proteins Genes Goals Grant Human IGA Glomerulonephritis Imaging Techniques In Vitro Injury International Island Kidney Kidney Diseases Knock-out Knockout Mice Maintenance Mediator of activation protein Medical Mentors Modeling Mus Nephrology Pathway interactions Patient Care Patients Phenotype Phosphotransferases Principal Investigator Property Protamines Protein Overexpression Proteins Proteinuria Regulation Renal glomerular disease Reporting Research Role Scientist Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Stress Fibers Testing Training Training Activity Transforming Growth Factor beta Transgenic Mice United States National Institutes of Health Up-Regulation Work Writing base career development cell injury chromatin immunoprecipitation glomerulosclerosis human disease improved in silico in vivo knock-down medical schools mid-career faculty news novel novel therapeutic intervention overexpression podocyte promoter protein expression skills slit diaphragm synaptopodin targeted treatment therapeutic target transcription factor urinary

项目摘要

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.

项目摘要：尽管人们接受肾小球足细胞作为蛋白尿肾损伤的靶细胞细胞特异性治疗在临床肾病学中仍然缺乏，一个关键障碍是对细胞特异性治疗的了解有限。我们的初步数据已确定 KIBRA（肾脑蛋白）是一种疾病期间足细胞损伤的机制。 KIBRA 的表达在人类疾病中增加，而在人类疾病中 KIBRA 沉默。我们已经证明 KIBRA 可以抑制 Hippo 的信号传导。途径效应子 Yes 相关蛋白 (YAP) 并破坏正常的肌动蛋白细胞骨架动力学表达。在 Tgfbr1 转基因小鼠和 CD2AP 敲低足细胞中也有所增加，我们的中心假设是 TGF-β。 β/Smad 信号传导导致足细胞中 KIBRA 上调，导致足细胞损伤。相关联，我们发现 KIBRA 过度表达足以诱导和促进肾小球疾病进展，而慢性肾小球疾病模型中 KIBRA 缺失将具有保护作用。拟议的研究表明，定义 KIBRA 在肾小球疾病进展中的作用将增加对肾小球疾病进展的理解足细胞损伤的机制并推进对靶向治疗的探索我们的假设将通过三个方面进行检验。具体目标：目标 1 将定义足细胞中 KIBRA 表达增加的上游调节。目标 2 将确定足细胞中 KIBRA 过度表达是否会促进体内肾小球疾病进展。目标 3 将确定 KIBRA 缺失是否会减少慢性肾小球疾病中的足细胞损伤。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。 Meliambro 提议的培训活动涉及四个领域：1）肾小球疾病、急性肾损伤的动物模型 (AKI) 和慢性肾病 (CKD)；2) 足细胞生物学和细胞信号传导，重点关注河马信号通路；3）先进的成像技术；4）科学写作和演讲技巧。为了实现这一目标，她组建了一支由医学部主任何慈江博士领导的指导和咨询团队。肾脏病学和伊坎肾脏病学奖学金项目副教授兼主任 Kirk Campbell 博士西奈山医学院 (ISMMS) 的 He 博士和 Campbell 博士都是前 K08 获奖者，共有 4 名获奖者。 R01 资助在足细胞细胞生物学领域拥有专业知识的人。环境：ISMMS 在医疗和科学培训、生物医学研究和患者治疗方面处于国际领先地位。研究是重中之重，根据《美国新闻与世界报道》和《美国国家卫生研究院》的资助，ISMMS 在美国医学院中排名第 13 位。世界报告和美国医学院协会每位主要研究者的研究经费排名第二 (AAMC) ISMMS 肾脏科在研究方面处于国际领先地位，特别是在以下领域：足细胞细胞生物学。