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：
10308506
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/10308506
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 Injury Injury to Kidney Ischemia Kidney Kidney Diseases Ligand Binding Domain Ligands Macrophage Activation Mediating Mediation Mediator of activation protein Membrane Myelogenous Myeloid Cells Myofibroblast Organ Peptide Hydrolases Pharmacology 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 macrophage member prevent receptor receptor expression renal damage 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，该家族由胞外配体结合结构域、单个跨膜区域、同源胞质蛋白酪氨酸激酶结构域和具有多个磷酸化位点的 C 末端尾部。 EGFR 可以被激活结合并诱导的配体家族（包括 EGF、TGF-a、HB-EGF、双调蛋白、上皮调节蛋白和 betacellulin）受体自身磷酸化和细胞内信号通路的激活。 EGFR 的反式激活受体通过激活 ADAM 介导的裂解和活性 EGFR 配体的释放而发生，ADAM17 (TACE) 介导 HB-EGF、双调蛋白、TGF-a 和表皮调节蛋白的释放。我们和其他人已经报告了 EGFR 是慢性进行性肾病纤维化的介质，包括糖尿病肾病、RPGN、慢性肾病同种异体移植肾病和 PKD。 EGFR 激活的遗传或药物抑制可能是有效的进行性肾病实验模型的治疗干预，但其机制 EGFR 激活介导进行性慢性肾损伤的发展尚不完全清楚。 EGFR 及其配体在多种细胞类型中表达，包括骨髓来源的细胞。我们和其他人已经确定了骨髓来源的细胞在急性肾损伤的传播和慢性肾损伤的发展，但肾髓细胞 EGFR 及其配体在进行性肾损伤中的作用此前尚未研究过肾损伤。我们最近的初步研究表明 EGFR 信号传导是一种肾脏中炎症巨噬细胞作用的介质。如初步结果所示，激活骨髓 EGFR 及其配体双调蛋白 (AREG) 的表达似乎在缺血后肾损伤和进行性肾纤维化的发展。此外，最近的研究证明 iRhom2（菱形膜内蛋白酶家族的非活性成员）介导骨髓细胞特异性激活 TACE 并分泌双调蛋白和 HB-EGF 以及 TNF-a 不影响其他器官中的配体释放，这增加了靶向 iRhom2 可能是一种可能性限制 CKD 发生或进展的潜在有效方法。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：目标 I 确定 EGFR 在肾脏疾病巨噬细胞激活中的作用目标 II 确定双调蛋白在介导进行性肾小管间质纤维化发展中的作用肾损伤目标 III 确定 iRhom2（Rhomboid 5 同源物 2 (RHBDF2)）激活在肾骨髓细胞介导中的作用细胞介导的肾小管间质纤维化