Role of Collagen Binding Receptors in Glomerulosclerosis

点击翻译按钮获取中文摘要

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.