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

基本信息

批准号：
7934535
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
项目类别：
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/7934535
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 Instruction 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 receptor research study response response to injury selective expression skills slit diaphragm stem therapy design ubiquitin-protein ligase

项目摘要

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。足细胞形成血尿界面的最终过滤屏障，是受糖尿病肾病和其他非糖尿病肾小球肾病影响的主要细胞类型。由于细胞死亡或脱离而导致的足细胞损失与肾小球疾病的进展直接相关。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。在肾小球疾病动物模型中，足细胞选择性上调胶质细胞系源性神经营养因子 (GDNF) 及其受体酪氨酸激酶 Ret。 GDNF 是神经元的有效生存因子，因其在帕金森病中的治疗前景而受到深入研究。我们证明，在体外足细胞损伤模型中，足细胞受到 GDNF 的保护。我们假设 GDNF-Ret 信号通路对于足细胞体内损伤的发育、维持和恢复至关重要。具体来说，我将：(1) 检验 GDNF-Ret 信号通路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 作为一种适应性反应来阻止肾小球进展的假设(3) 检验以下假设：Cbl-3 是由 CD2AP 控制的 E3 连接酶，负责 Ret 降解和信号转导。我的目标是通过了解该通路及其衔接分子的生理功能，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，让我获得成为领导自己的研究实验室的独立临床科学家所需的基础科学培训和科学知识。我的目标还包括培养独立批判性思维、写作以及创新实验和问题规划所需的技能。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病学部在足细胞生物学方面广泛而深入的知识和专业知识。公共健康相关性：临床和基础科学研究表明，足细胞是许多成人肾脏疾病进展为慢性和终末期肾脏疾病的主要损伤目标。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，目的是使这些知识有助于新治疗策略的开发。