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

描述(由申请人提供)： 在美国，肾小球疾病是成人慢性和终末期肾脏疾病的最常见原因。足细胞是糖尿病肾病和其他非糖尿病肾小球疾病的主要细胞类型，在血尿界面形成最终的滤过屏障。足细胞丢失，无论是由于细胞死亡或脱落，都与肾小球疾病的进展直接相关。因此，了解足细胞如何发展和对损伤做出反应对于合理设计治疗干预措施至关重要。在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是一种强大的神经元生存因子，由于其在帕金森病中的治疗前景而得到了广泛的研究。我们证明了在体外足细胞损伤模型中，GDNF对足细胞具有保护作用。我们假设GDNF-Ret信号通路在体内足细胞的发育、维持和损伤恢复中起关键作用。具体地说，我将：(1)测试GDNF-Ret信号通路对于足细胞和肾小球功能的发育和维持是必需的假设，(2)测试GDNF作为适应性反应在体内防止肾小球疾病进展的假设，以及外源性GDNF的应用是一种治疗干预，以及(3)测试Cbl-3是由CD2AP控制的E3-连接酶，负责Ret的降解和信号传递。我的目标是，通过了解这一通路及其接头分子的生理功能，将确定肾小球疾病的新治疗靶点。这笔赠款将为我提供必要的支持，让我获得基本的科学培训和科学知识，成为一名领导我自己的研究实验室的独立临床科学家。我的目标也是培养独立批判性思维、写作以及计划创新实验和问题所需的技能。我很幸运地得到了我的导师Lawrence Holzman博士的指导，以及密歇根大学肾脏学部在足细胞生物学方面的共同广度和深度的知识和专业知识。 公共卫生相关性：临床和基础科学研究表明，在许多发展为慢性和终末期肾脏疾病的成人肾脏疾病中，足细胞是主要的损伤靶点。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，以期这些知识将促进新的治疗策略的发展。

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.