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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）：