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：尽管接受肾小球足细胞作为蛋白尿肾脏损伤的靶细胞疾病，细胞特异性疗法在临床肾病学中仍然没有。关键的障碍是对疾病期间足细胞损伤的机制。我们的初步数据已将Kibra（肾脏脑蛋白）确定为足细胞损伤的潜在介体。 Kibra的表达在人类疾病中增加，而Kibra的沉默足细胞在体外和体内受到保护。我们已经证明Kibra抑制了河马的信号途径效应子与YES相关蛋白（YAP）并破坏正常肌动蛋白细胞骨架动力学。 Kibra表达是 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/SMAD信号传导导致足细胞中的基布拉上调，导致足细胞损伤。另外，作为一种疾病相关，我们假设Kibra过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的Kibra缺失将受到保护。理由拟议的研究是，定义基布拉在肾小球疾病进程中的作用将增加对足细胞损伤的机制，并提高了对靶向治疗的追求。我们的假设将通过三个具体目的： AIM 1将定义上游的上游调节足细胞中Kibra表达的增加。 AIM 2将确定足细胞中的Kibra过表达是否促进体内肾小球疾病的进展。 AIM 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：本申请的主要目的是支持克里斯汀·梅利亚姆布（Kristin Meliambro）博士的职业发展成足细胞生物学和肾小球疾病领域的独立基础科学家。博士 Meliambro提议的培训活动在四个领域：1）肾小球疾病的动物模型，急性肾脏损伤（AKI）和慢性肾脏疾病（CKD）； 2）足细胞细胞生物学和细胞信号传导，重点是河马信号通路； 3）高级成像技术； 4）科学写作和演讲技巧。为了实现这一目标，她组建了一个由约翰·西安格（John Cijiang）博士领导的心理和咨询团队。肾脏科和肾脏学副教授兼肾脏研究金计划主任柯克·坎贝尔博士西奈山（ISMMS）医学院。两个博士。他和坎贝尔是前K08获奖者，共有四个他们之间在足细胞生物学领域具有专业知识的R01赠款。环境：ISMM是医学和科学培训，生物医学研究和患者的国际领导者关心。研究是当务之急，因为美国新闻和美国医学院协会的首席研究人员的世界报告和第二笔研究资金（AAMC）。 ISMMS肾脏科学划分是研究的国际领导者，尤其是在足细胞生物学。