Mechanisms of EGFR Activation and Signaling in Kidney Disease

肾脏疾病中 EGFR 激活和信号转导的机制

基本信息

批准号：
10543051
负责人：
RAYMOND C. HARRIS
金额：
$ 59.85万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543051
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Affect Amphiregulin Binding C-terminal Cells Chronic Chronic rejection of renal transplant Cytoplasmic Protein DTR gene Dendritic Cells Development Diabetic Nephropathy EGF gene Epidermal Growth Factor Receptor Epiregulin ErbB Receptor Family Protein Experimental Models Family Family member Fibroblasts Fibrosis Genetic Homologous Gene Inflammation Inflammation Mediators Inflammatory Injury Injury to Kidney Ischemia Kidney Kidney Diseases Ligand Binding Domain Ligands Macrophage Macrophage Activation Mediating Mediation Mediator Membrane Myelogenous Myeloid Cells Myofibroblast Organ Peptide Hydrolases Phenotype Phosphorylation Site Play Receptor Activation Receptor Signaling Recovery Reperfusion Therapy Reporting Role Signal Pathway Source TNF gene Tail Therapeutic Intervention Transactivation Transforming Growth Factor alpha Tyrosine Kinase Domain betacellulin cell type cytokine extracellular ischemic injury kidney fibrosis member pharmacologic prevent receptor receptor expression renal damage renal ischemia rhomboid therapeutically effective

项目摘要

The Epidermal Growth Factor Receptor (EGFR) is a member of the family of ErbB receptors, which consist of an extracellular ligand-binding domain, a single membrane-spanning region, a homologic cytoplasmic protein tyrosine kinase domain and a C-terminal tail with multiple phosphorylation sites. EGFR can be activated by a family of ligands (including EGF, TGF-a, HB-EGF, amphiregulin, epiregulin and betacellulin) that bind and induce receptor autophosphorylation and activation of intracellular signaling pathways. Transactivation of the EGFR receptor occurs by activation of ADAM-mediated cleavage and release of active EGFR ligands, with ADAM17 (TACE) mediating release of HB-EGF, amphiregulin, TGF-a and epiregulin. We and others have reported EGFR to be a mediator of fibrosis in chronic progressive kidney disease, including diabetic nephropathy, RPGN, chronic allograft nephropathy and PKD. Either genetic or pharmacologic inhibition of EGFR activation can be an effective therapeutic intervention in experimental models of progressive kidney disease, but the mechanisms by which EGFR activation mediates development of progressive chronic kidney injury are still incompletely understood. EGFR and its ligands are expressed in a variety of cell types including cells of myeloid origin. We and others have defined an important role for myeloid derived cells in propagation of acute kidney injury and in the development of chronic renal damage, but the role of renal myeloid cell EGFR and its ligands in progressive kidney injury has not been previously studied. Our recent preliminary studies indicate that EGFR signaling is a mediator of inflammatory macrophage actions in the kidney. As indicated in Preliminary Results, activation of myeloid EGFR as well as expression of its ligand, amphiregulin (AREG), appear to play an important role in post-ischemic renal injury and in development of progressive renal fibrosis. In addition, recent studies demonstrate that iRhom2, an inactive member of the Rhomboid intramembrane proteinase family, mediates myeloid cell-specific activation of TACE and secretion of amphiregulin and HB-EGF, as well as TNF-a without affecting ligand release in other organs, raising the possibility that targeting iRhom2 could be a potentially efficacious approach to limit development or progression of CKD. We propose to investigate the role of the renal myeloid EGFR axis in development of chronic renal fibrosis in three specific aims: Aim I Determine the role of EGFR in macrophage activation in kidney disease Aim II Determine the role of amphiregulin in mediation of development of tubulointerstitial fibrosis with progressive kidney injury Aim III Determine the role of iRhom2 (Rhomboid 5 homolog 2 (RHBDF2)) activation in mediation of renal myeloid cell-mediated tubulointerstitial fibrosis

表皮生长因子受体（EGFR）是ERBB受体家族的成员，该家族组成细胞外配体结合结构域，单个膜跨膜区域，一种同源性细胞质蛋白酪氨酸激酶结构域和具有多个磷酸化位点的C末端。 egfr可以被a激活结合和诱导的配体家族（包括EGF，TGF-A，HB-EGF，Amphiregulin，Epiregulin和betacellulin）受体自磷酸化和细胞内信号通路的激活。 EGFR的反式激活受体通过ADAM介导的裂解的激活和活性EGFR配体的释放而发生，ADAM17发生（TACE）介导HB-EGF，两次两次凝胶蛋白，TGF-A和环保蛋白的释放。我们和其他人报告了EGFR 成为慢性进行性肾脏疾病的纤维化中介，包括糖尿病性肾病，RPGN，慢性同种异体肾病和PKD。 EGFR激活的遗传或药理抑制可能是有效的在进行性肾脏疾病的实验模型中进行治疗干预，但其机制 EGFR激活介导了进行性慢性肾损伤的发展，但仍未完全理解。 EGFR及其配体以多种细胞类型表达，包括髓样起源的细胞。我们和其他人已经定义了髓样衍生细胞在急性肾损伤传播和慢性肾脏损害的发展，但肾髓样细胞EGFR及其配体的作用肾脏损伤以前尚未被研究。我们最近的初步研究表明，EGFR信号是一个肾脏炎症性巨噬细胞作用的介体。如初步结果所示，激活髓样EGFR及其配体的表达，两极分裂蛋白（AREG）似乎在缺血后的肾脏损伤和进行性肾纤维化的发展。此外，最近的研究证明菱形内膜内蛋白酶家族的不活跃成员IRHOM2介导 TACE的粒细胞特异性激活和分泌的两极分子和HB-EGF以及TNF-A 不影响其他器官中的配体释放，提高了靶向IRHOM2可能是一个可能性的可能性限制CKD发展或发展的潜在有效方法。我们建议研究肾髓样EGFR轴在慢性肾纤维化发展中的作用三个具体目标：目的我确定EGFR在巨噬细胞激活中的作用在肾脏疾病中 AIM II确定两极分学蛋白在逐渐进行性纤维化发展中的作用肾脏受伤 AIM III确定IRHOM2（Rhomboid 5同源2（RHBDF2））激活在肾髓样介导中的作用细胞介导的微管间隙纤维化