GDNF and Ret are critical for glomerular development, maintenance, and protection

GDNF 和 Ret 对于肾小球发育、维持和保护至关重要

• 批准号: 7707424
• 负责人: Cynthia Tsui
• 金额: $ 15.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7707424
• 关键词: Adult; Affect; Amyotrophic Lateral Sclerosis; Animal Model; Apoptosis; Basic Science; Biology; Blood; CD2-associated protein; Cell Death; Cell Proliferation; Cells; Chronic; Cicatrix; Clinical; Complex; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Down-Regulation; Embryo; End stage renal failure; Epidermal Growth Factor; Fab Immunoglobulins; Filtration; Focal Segmental Glomerulosclerosis; Functional disorder; Genes; Genetic; Goals; Grant; Growth; Growth Factor; Half-Life; Health; Histologic; Immune; Immunologics; In Vitro; Injury; Investigation; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; Knowledge; Laboratory Research; Maintenance; Mediating; Membranous Glomerulonephritis; Mentors; Metanephric Diverticulum; Michigan; Modeling; Molecular; Monitor; Morphogenesis; Nephrology; Nephrosis; Nervous system structure; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathway interactions; Perinatal; Physiological; Platelet-Derived Growth Factor; Predisposition; Prevalence; Principal Investigator; Process; Proteins; Proteinuria; Puromycin Aminonucleoside; Rattus; Receptor Protein-Tyrosine Kinases; Recombinants; Recovery; Renal function; Renal glomerular disease; Rodent Model; Scientist; Signal Pathway; Signal Transduction; Techniques; Testing; Therapeutic; Therapeutic Intervention; Thinking; Training; Universities; Up-Regulation; Urine; Writing; base; cell type; design; glial cell-line derived neurotrophic factor; glomerular function; glomerulosclerosis; in vivo; injured; innovation; multicatalytic endopeptidase complex; new therapeutic target; non-diabetic; novel therapeutics; podocyte; postnatal; prevent; protective effect; public health relevance; receptor; research study; response; response to injury; selective expression; skills; slit diaphragm; stem; therapy design; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Glomerular diseases are the most common cause of adult chronic and end stage renal diseases in the US. Podocytes, which form the final filtration barrier at the blood-urine interface, are the predominant cell type affected by diabetic nephropathy and other non-diabetic glomerular kidney diseases. Podocyte loss, either by cell death or detachment, is directly related to the progression of glomerular disease. Thus, understanding how podocytes develop and respond to injury is critical for the rational design of therapeutic interventions. Glial cell line-derived neurotrophic factor (GDNF) and its receptor tyrosine kinase, Ret, are upregulated selectively by podocytes in animal models of glomerular disease. GDNF is a potent survival factor for neurons and has been studied intensively because of its therapeutic promise in Parkinson's disease. We demonstrated that podocytes are protected by GDNF during in vitro podocyte injury models. We hypothesize that the GDNF-Ret signaling pathway is critical for the development, maintenance, and recovery of podocytes to injury in vivo. Specifically, I will: (1) test the hypothesis that the GDNF-Ret signaling pathway is required for the development and maintenance of podocytes and glomerular function, (2) test the hypothesis that GDNF functions as an adaptive response to prevent the progression of glomerular diseases in vivo, and that the administration of exogenous GDNF is a therapeutic intervention, and (3) test the hypothesis that Cbl-3 is the E3-ligase controlled by CD2AP that is responsible for Ret degradation and signaling. It is my goal that by understanding the physiologic function of this pathway and its adaptor molecules, novel therapeutic targets for glomerular disease will be identified. This grant will provide the support necessary for me to acquire the basic science training and scientific knowledge necessary to become an independent clinician scientist leading my own research laboratory. My goal is also to develop the skills necessary for independent critical thinking, writing, and the planning of innovative experiments and questions. I am fortunate to have the guidance of my mentor, Dr. Lawrence Holzman, and the collective breadth and depth of knowledge and expertise in podocyte biology from the Nephrology Division at University of Michigan. PUBLIC HEALTH RELEVANCE: Clinical and basic science studies have demonstrated that podocytes are the main target of injury in many adult kidney diseases that progress to chronic and end stage renal diseases. The goal of our proposal is to understand these mechanisms and to discover molecules controlling the growth and health of the podocyte with the intent that this knowledge will facilitate the development of new therapeutic strategies.

描述（由申请人提供）： 肾小球疾病是美国成人慢性和终末期肾病的最常见原因。足细胞是糖尿病肾病和其他非糖尿病性肾小球性肾病的主要细胞类型，在血-尿界面形成最终的过滤屏障。足细胞的损失，无论是通过细胞死亡或脱离，是直接相关的肾小球疾病的进展。因此，了解足细胞如何发育和对损伤的反应对于合理设计治疗干预措施至关重要。肾小球疾病动物模型中足细胞选择性上调胶质细胞源性神经营养因子（GDNF）及其受体酪氨酸激酶Ret。GDNF是一种有效的神经元存活因子，由于其在帕金森病中的治疗前景而被深入研究。我们证明了在体外足细胞损伤模型中，GDNF对足细胞有保护作用。我们假设GDNF-Ret信号通路对于足细胞在体内损伤的发展、维持和恢复至关重要。具体而言，我将：（1）检验GDNF-Ret信号传导途径是足细胞和肾小球功能的发育和维持所必需的假设，（2）检验GDNF作为适应性反应发挥作用以防止体内肾小球疾病进展的假设，以及外源性GDNF的施用是治疗性干预的假设，和（3）检验Cbl-3是由负责Ret降解和信号传导的CD 2AP控制的E3连接酶的假设。我的目标是通过了解这一途径及其衔接分子的生理功能，将确定新的肾小球疾病的治疗靶点。这笔赠款将提供必要的支持，使我获得必要的基础科学培训和科学知识，成为一名独立的临床科学家，领导我自己的研究实验室。我的目标也是培养独立批判性思维，写作和创新实验和问题的规划所需的技能。我很幸运能够得到我的导师Lawrence Holzman博士的指导，以及密歇根大学肾脏科在足细胞生物学方面的知识和专业知识的集体广度和深度。 公共卫生关系：临床和基础科学研究表明，足细胞是许多发展为慢性和终末期肾病的成人肾脏疾病的主要损伤靶点。我们建议的目标是了解这些机制，并发现控制足细胞生长和健康的分子，目的是这些知识将促进新的治疗策略的发展。