Role of Collagen Binding Receptors in Glomerulosclerosis

胶原结合受体在肾小球硬化中的作用

基本信息

批准号：
8971990
负责人：
AMBRA POZZI
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8971990
关键词：
Ablation Binding Cell Proliferation Cell physiology Cells Cessation of life Chemicals Chronic Myeloid Leukemia Collagen Collagen Receptors Collagen Type IV Communication Computer Simulation DDR1 gene Dasatinib Data Deposition Diabetes Mellitus Diabetic Nephropathy Disease Docking End stage renal failure Endothelial Cells Experimental Models Extracellular Matrix Fibrosis Generations Genetic Glucose Goals Grant Health Homeostasis Hypertension In Vitro Inherited Injury Insulin-Dependent Diabetes Mellitus Kidney Knockout Mice Laboratories Ligands Mediating Molecular Molecular Weight Morbidity - disease rate Mus Nodular glomerulosclerosis Patients Pharmaceutical Preparations Phosphotransferases Physiological Prevention Process Proteinuria Receptor Activation Receptor Protein-Tyrosine Kinases Renal function Renal glomerular disease Reporting Role Sclerosis Structure Systemic Scleroderma Testing Time Tissues Translating Tyrosine Kinase Inhibitor Up-Regulation Veterans base cell type clinically relevant diabetic discoidin domain receptor 1 effective therapy functional loss genetic approach glomerular function glomerulosclerosis in vivo inhibitor/antagonist insight kinase inhibitor loss of function mesangial cell migration mortality novel novel therapeutic intervention podocyte prevent receptor receptor binding tyrosine receptor

项目摘要

DESCRIPTION (provided by applicant): Our long term goal is to understand the mechanisms that underlie the modulation of collagen turnover in the diabetic glomerulus in order to devise more effective therapies to prevent diabetic glomerulosclerosis. In diabetes, the deposition of matrix components (mainly collagens) within the glomeruli increases thus leading to loss of functional glomeruli and end-stage renal disease. Interaction between glomerular cells with the surrounding matrix has emerged as a key factor involved in the control of matrix homeostasis as well as initiation and progression to fibrosis. Cell-extracellular matrix interactions are made possible by various cellular receptors, including Discoidin Domain Receptor (DDR)-1, a receptor tyrosine kinase activated by collagen and a key regulator of matrix homeostasis. In healthy glomeruli DDR1 is usually undetectable; however, its expression, together with that of collagens, is upregulated in glomeruli injury. The question of whether the upregulation of DDR1 is beneficial to counteract fibrosis or is deleterious and contributes to fibrosis is still unresolved. Results from our laboratory and others suggest that loss of DDR1 is beneficial in the course of renal injury, as DDR1-null mice are protected against glomerular injury induced by partial renal ablation, hypertension, or hereditary collagen IV disease. This protection is accompanied by reduced deposition of glomerular collagens and overall reduced proteinuria. In addition, we provide evidence that mesangial cells lacking DDR1 secrete less collagen than wild type cells. Based on these findings, the overall goal of this VA Merit renewal is to understand the role of DDR1 in glomerular disease and define whether blocking its function is beneficial for the treatment of glomerulosclerosis. We hypothesize that upregulation of DDR1 and its natural ligands collagens contributes to diabetes-mediated glomerular injury by promoting excessive DDR1-dependent matrix synthesis. The aims of this grant are: Aim 1. Determine the role of DDR1 in the progression of diabetic glomerular injury. Since loss of DDR1 results in decreased glomerular damage and matrix deposition following injury, we hypothesize that DDR1 is a critical modulator of glomerular injury and its loss/inhibition is protective in the course of diabetes-mediated glomerular damage. A genetic approach (use of DDR1-null mice) and a pharmacological approach (use of a commercially available DDR1 inhibitor) will be used to determine in vivo the role of this receptor in diabetic glomerulopathy. Aim 2. Determine the molecular mechanism(s) whereby DDR1 modulates collagen synthesis in diabetic glomerular injury. We hypothesize that following injury, increased activation of DDR1 by collagen leads to uncontrolled collagen deposition and consequent glomerulosclerosis. In this aim we will 1) analyze how DDR1/collagen interactions control collagen synthesis; 2) determine whether inhibition of DDR1 prevents collagen synthesis; and 3) devise new highly selective and potent small molecular weight non-peptide DDR1 kinase inhibitors. We believe this study will generate novel insights into the molecular basis whereby DDR1 regulates collagen synthesis in diabetic nephropathy. In addition, the generation of highly selective and potent DDR1 inhibitors could provide a completely novel therapeutic approach for the treatment and ideally prevention of diabetic nephropathy.

描述（由申请人提供）：我们的长期目标是了解糖尿病肾小球胶原更新调节的机制，以便设计出更有效的疗法来预防糖尿病肾小球硬化。在糖尿病中，肾小球内基质成分（主要是胶原蛋白）的沉积增加，从而导致肾小球功能丧失和终末期肾病。肾小球细胞与周围基质之间的相互作用已成为控制基质稳态以及纤维化起始和进展的关键因素。细胞-细胞外基质相互作用是通过各种细胞受体实现的，包括盘状蛋白结构域受体 (DDR)-1，一种由胶原蛋白激活的受体酪氨酸激酶，也是基质稳态的关键调节剂。在健康的肾小球中，DDR1 通常检测不到；然而，它的表达与胶原蛋白的表达一起，在肾小球损伤中上调。 DDR1 的上调是否有益于对抗纤维化，还是有害并导致纤维化的问题仍悬而未决。我们实验室和其他实验室的结果表明 DDR1 的缺失在肾损伤过程中是有益的，因为 DDR1 缺失的小鼠可以免受部分肾脏消融、高血压或遗传性 IV 型胶原蛋白疾病引起的肾小球损伤。这种保护伴随着肾小球胶原蛋白沉积的减少和总体蛋白尿的减少。此外，我们提供的证据表明，缺乏 DDR1 的肾小球系膜细胞分泌的胶原蛋白比野生型细胞少。基于这些发现，此次 VA Merit 更新的总体目标是了解 DDR1 在肾小球疾病中的作用，并确定阻断其功能是否有利于治疗肾小球硬化症。我们假设 DDR1 及其天然配体胶原蛋白的上调通过促进过度的 DDR1 依赖性基质合成而导致糖尿病介导的肾小球损伤。该资助的目的是：目标 1. 确定 DDR1 在糖尿病肾小球损伤进展中的作用。由于 DDR1 的缺失会导致损伤后肾小球损伤和基质沉积减少，因此我们假设 DDR1 是肾小球损伤的关键调节剂，并且它的缺失/抑制在糖尿病介导的肾小球损伤过程中具有保护作用。将使用遗传方法（使用 DDR1 缺失小鼠）和药理学方法（使用市售 DDR1 抑制剂）来确定该受体在糖尿病肾小球病中的体内作用。目标 2. 确定 DDR1 在糖尿病肾小球损伤中调节胶原蛋白合成的分子机制。我们假设损伤后，胶原蛋白对 DDR1 的激活增加，导致胶原蛋白沉积不受控制，进而导致肾小球硬化。为此，我们将 1) 分析 DDR1/胶原蛋白相互作用如何控制胶原蛋白合成； 2)确定抑制DDR1是否会阻碍胶原蛋白的合成； 3) 设计新的高选择性和有效的小分子量非肽 DDR1 激酶抑制剂。我们相信这项研究将为 DDR1 调节糖尿病肾病胶原蛋白合成的分子基础提供新的见解。此外，高选择性和有效的DDR1抑制剂的产生可以为糖尿病肾病的治疗和理想的预防提供一种全新的治疗方法。