Role of Collagen Binding Receptors in Glomerulosclerosis

描述（由申请人提供）： 我们的长期目标是了解糖尿病肾小球中胶原蛋白周转调节的机制，以设计更有效的治疗方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）的沉积增加，从而导致功能性肾小球的丧失和终末期肾病。肾小球细胞与周围基质之间的相互作用已成为参与基质稳态控制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通过各种细胞受体而成为可能，包括盘状结构域受体（DDR）-1，一种由胶原激活的受体酪氨酸激酶和基质稳态的关键调节剂。 在健康的肾小球中，DDR 1通常是检测不到的;然而，它的表达与胶原蛋白一起在肾小球损伤中上调。DDR 1的上调是否有益于对抗纤维化或有害并有助于纤维化的问题仍未解决。我们实验室和其他实验室的结果 表明DDR 1缺失在肾损伤过程中是有益的，因为DDR 1缺失小鼠被保护免于由部分肾消融、高血压或遗传性胶原IV疾病诱导的肾小球损伤。这种保护作用伴随着肾小球胶原沉积减少和蛋白尿总体减少。此外，我们提供的证据表明，缺乏DDR 1的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DDR 1在肾小球疾病中的作用，并确定阻断其功能是否有利于肾小球硬化症的治疗。我们推测DDR 1及其天然配体胶原蛋白的上调通过促进过度的DDR 1依赖性基质合成而促进糖尿病介导的肾小球损伤。该补助金的目标是：目标1。确定DDR 1在糖尿病肾小球损伤进展中的作用。由于DDR 1的丢失导致损伤后肾小球损伤和基质沉积减少，因此我们假设DDR 1是肾小球损伤的关键调节剂，并且其丢失/抑制在糖尿病介导的肾小球损伤过程中具有保护作用。将使用遗传学方法（使用DDR 1缺失小鼠）和药理学方法（使用市售DDR 1抑制剂）在体内确定该受体在糖尿病性肾小球病中的作用。目标2.确定DDR 1调节糖尿病肾小球损伤中胶原合成的分子机制。我们推测，损伤后，增加激活的DDR 1的胶原蛋白导致不受控制的胶原蛋白沉积和随之而来的肾小球硬化。在这个目标中，我们将1）分析DDR 1/胶原蛋白相互作用如何控制胶原蛋白合成; 2）确定DDR 1的抑制是否阻止胶原蛋白合成;和3）设计新的高选择性和有效的小分子量非肽DDR 1激酶抑制剂。 我们相信，这项研究将产生新的见解的分子基础，DDR 1调节胶原蛋白的合成在糖尿病肾病。此外，高选择性和有效的DDR 1抑制剂的产生可以为治疗和理想地预防糖尿病肾病提供一种全新的治疗方法。

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.