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

GDNF 和 Ret 对于肾小球的发育、维持和保护至关重要

• 批准号: 8536263
• 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/8536263
• 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 Sciences; 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

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 forthe 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 forthe 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. RELEVANCE (See instructions): 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.

肾小球疾病是美国成年慢性和终阶段肾脏疾病的最常见原因。 足细胞在血液界面上形成最终的过滤屏障，是主要的细胞类型 受糖尿病性肾病和其他非糖尿病性肾小球肾脏疾病的影响。可以损失足细胞 通过细胞死亡或脱离，与肾小球疾病的进展直接相关。因此，理解 足细胞如何发展和应对损伤对于治疗干预的合理设计至关重要。 神经胶质细胞系衍生的神经营养因子（GDNF）及其受体酪氨酸激酶RET，上调 在肾小球疾病的动物模型中有选择性地通过足细胞。 GDNF是有效的生存因子 神经元并因其在帕金森氏病的治疗诺言而进行了深入研究。我们 证明足细胞在体外足细胞损伤模型中受到GDNF的保护。我们假设 GDNF-RET信号通路对于开发，维护和恢复至关重要 体内受伤的足细胞。具体而言，我将：（1）检验以下假设：GDNF-RET信号通路为 开发和维持足细胞和肾小球功能所必需的，（2）检验假设 该GDNF作为适应性反应，以防止体内肾小球疾病的进展，并且 外源GDNF的给药是一种治疗性干预措施，（3）检验了CBL-的假设 3是由CD2AP控制的E3 - 连接酶，负责R​​ET降解和信号传导。这是我的目标 通过了解该途径的生理功能及其适配器分子，新型治疗 将确定肾小球疾病的靶标。这笔赠款将为我提供必要的支持 获得成为独立临床医生所必需的基础科学培训和科学知识 科学家领导自己的研究实验室。我的目标也是发展独立所需的技能 批判性思维，写作以及创新实验和问题的计划。我很幸运有 我的导师劳伦斯·霍尔茨曼（Lawrence Holzman）博士的指导以及知识的集体广度和深度 密歇根大学肾脏科学系的足细胞生物学专业知识。 相关性（请参阅说明）： 临床和基础科学研究表明，足细胞是许多损伤的主要目标 成人肾脏疾病会发展为慢性和末期肾脏疾病。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 考虑到这些知识将有助于发展新的治疗策略。