Chronic kidney disease is a major health problem in the United States today, as more than 20 million people have abnormalities in kidney function, and the incidence is rising at epidemic proportions and over half a million Americans will be on dialysis by 2010. Diseases of the glomerulus account for over 60% of all cases of end stage renal disease, the most important of which is diabetic nephropathy. Although glomerular disease has multiple etiologies, the final pathology is glomerulosclerosis, characterized by uncontrolled collagen IV synthesis and deposition. One of the key processes that regulate collagen IV homeostasis is the interaction of glomerular cells with collagen, particularly via integrins a1?1 and a2?1. Little is known about the structure at the atomic level of the collagen matrices, their receptors, and the molecular mechanisms whereby integrin/collagen interactions control collagen homeostasis in glomerular disease. The overall hypothesis of this Program Project is that interactions of integrins a1?1 and a2?1 with the a1a2a1 and a3a4a5 collagen IV networks are critical to mediating signaling that influences cell behavior. Specific inter- and intra-molecular interactions, at the atomic level, are required for normal glomerular function whereas perturbation of these specific interactions causes disease. Four different research projects will explore this hypothesis. Project 1 will define the structural determinants of collagen IV that govern network stability and integrin binding. Project 2 will determine the molecular mechanism whereby interaction of collagen IV with integrins a1?1 and/or a2?1 control mesangial collagen IV homeostasis. Project 3 will determine the structural basis whereby the transmembrane and cytoplasmic domains of integrin a1?1 and a2?1 mediate intracellular signaling upon collagen binding. Project 4 will determine the interrelationship between integrins and collagen IV networks in glomerular function. The PPG is designed to promote collaborations among nephrologists, collagen and integrin biologists together with structural biologists, which are supported by Administrative, Structural Biology and Matrix Biology Cores. These projects will result in novel insights into mechanisms of collagen IV homeostasis that can serve as a platform for the development of drug-based manipulations that may prove effective in inhibiting and, ideally, preventing glomerulosclerosis.
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