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Crosstalk among Growth Factors, ADAMs and Integrins

生长因子、ADAM 和整合素之间的串扰

基本信息

批准号：
7995579
负责人：
MONIKA GOOZ
金额：
$ 5.4万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2009-12-16 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7995579
关键词：
Address Angiotensin II Area Basal lamina Cell physiology Cells Chronic Kidney Failure Clinical Trials Commit Coupled Data Disintegrin Domain ECM receptor EGF gene Environment Epidermal Growth Factor Receptor Event Extracellular Matrix Fibroblasts G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Glomerular Mesangial Cell Goals Growth Factor HTR2A gene Heparin Binding Integrins Kidney Ligands Mediating Mediator of activation protein Mentored Research Scientist Development Award Mentors Mentorship Metalloproteases Mitogen-Activated Protein Kinases Neoplasm Metastasis Pathway interactions Phagocytes Phenotype Physiological Play Principal Investigator Process Protein Tyrosine Kinase Receptor Activation Receptor Protein-Tyrosine Kinases Renal glomerular disease Research Resources Role Scientist Serotonin Signal Transduction Smooth Muscle Sphingosine-1-Phosphate Receptor TNF-alpha converting enzyme Thrombosis Training Transactivation Work angiogenesis inhibitor/antagonist insight knowledge base mesangial cell metalloenzyme novel therapeutics overexpression prevent programs receptor receptor coupling tumor

项目摘要

DESCRIPTION (provided by applicant): The goal of the present proposal is to study cross-talk between G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) that are present in physiological condition in renal mesangial cells. Specifically, we will study the involvement of metalloproteinases in this process. Further, we wish to study how extracellular matrix (ECM) receptors (called integrins) influence GPCR-RTK cross-talk in cultured mesangial cells. The specific aims of this proposal are: 1. To investigate whether activation of mitogenic Gq-coupled receptors (such as angiotensin II AT1A, serotonin 5-HT2A and LPA-Edg receptors) induce transactivation of the epidermal growth factor receptor (EGFR) by exogenous growth factor(s) through metalloproteinases in renal mesangial cells. a) If yes, we will examine whether these processes involve the same EGF-like growth factor (namely heparin-bound EGF) or whether distinct EGF-like growth factors are employed by the various GPCRs. b) We will also determine whether these shed ligands are processed by the same metalloproteinase(s), or by different ones depending on which GPCR is activated. Our initial focus will be on the TACE/ADAM 17 metalloproteinase. 2. To study the involvement of integrins and effects of changes in the ECM on GPCR-RTK cross-talk in mesangial cells. a) Is Gq-coupled receptor activation of ERK dependent on integrin-mediated cell anchorage? b) Which integrins are involved in GPCR-RTK cross-talk? c) Does overexpression of a TACE enzyme lacking the disintegrin domain alter signaling? d) Is physical interaction of TACE with integrins necessary for the GPCR-RTK cross-talk to occur?

描述（由申请人提供）：本研究的目的是研究生理条件下肾小球系膜细胞中G蛋白偶联受体（GPCR）和受体酪氨酸激酶（RTK）之间的相互作用。具体来说，我们将研究金属蛋白酶在这一过程中的参与。此外，我们希望研究细胞外基质（ECM）受体（称为整合素）如何影响培养的系膜细胞中的GPCR-RTK串扰。这项建议的具体目标是： 1. 研究促有丝分裂Gq偶联受体（如血管紧张素II AT 1A、5-羟色胺2A和LPA-Edg受体）的激活是否通过金属蛋白酶诱导外源性生长因子对肾小球系膜细胞表皮生长因子受体（EGFR）的反式激活。 a）如果是，我们将检查这些过程是否涉及相同的EGF样生长因子（即肝素结合的EGF），或者不同的EGF样生长因子是否被各种GPCR所利用。 B）我们还将确定这些脱落配体是由相同的金属蛋白酶加工还是由不同的金属蛋白酶加工，这取决于哪种GPCR被激活。我们最初的重点将是TACE/ADAM 17金属蛋白酶。 2. 目的研究肾小球系膜细胞整合素的参与及细胞外基质的变化对GPCR-RTK串扰的影响。 a）ERK的Gq偶联受体激活依赖于整合素介导的细胞锚定吗？ B）哪些整合素参与GPCR-RTK串扰？ c）缺乏去整合素结构域的TACE酶的过表达是否改变信号传导？ d）TACE与整合素的物理相互作用是否是发生GPCR-RTK串扰所必需的？