Cell-Matrix Interactions in the Glomerulus

慢性肾脏疾病是当今美国的一个主要健康问题， 人们的肾功能异常，发病率正在以流行病的比例上升， 到2010年将有50多万美国人接受透析治疗。肾小球疾病占 所有终末期肾病病例的60%，其中最重要的是糖尿病肾病。 虽然肾小球疾病有多种病因，但最终的病理是肾小球硬化， 其特征在于不受控制的胶原IV合成和沉积。其中一个关键的过程， 调节IV型胶原稳态是肾小球细胞与胶原的相互作用，特别是通过 整联蛋白α 1 α 1和α 2 α 1。对胶原基质原子水平的结构知之甚少， 它们的受体，以及整合素/胶原相互作用控制胶原的分子机制 肾小球疾病中的内稳态。本项目的总体假设是， 整合素α 1 α 1和α 2 α 1与α 1 α 2 α 1和α 3 α 4 α 5胶原IV网络的相互作用对于介导 影响细胞行为的信号。在原子上的特定分子间和分子内相互作用 水平，是正常肾小球功能所必需的，而这些特异性相互作用的干扰 导致疾病。四个不同的研究项目将探讨这一假设。项目1将定义 控制网络稳定性和整合素结合的IV型胶原蛋白的结构决定因素。项目2将 确定IV型胶原与整合素α 1 α 1和/或α 2 α 1相互作用的分子机制 控制系膜胶原IV稳态。项目3将确定结构基础， 整合素α 1 α 1和α 2 α 1的跨膜和胞质结构域介导细胞内信号传导 在胶原蛋白结合后。项目4将确定整合素和IV型胶原蛋白之间的相互关系 肾小球功能的网络。 PPG旨在促进肾病学家、胶原蛋白和整合素生物学家之间的合作 与结构生物学家一起，由行政，结构生物学和矩阵支持 生物学核心 这些项目将导致对胶原蛋白IV稳态机制的新见解， 作为开发基于药物的操作的平台， 理想情况下，还能预防肾小球硬化

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 alpha1alpha1 and alpha2alpha1. 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 alpha1alpha1 and alpha2alpha1 with the alpha1alpha2alpha1 and alpha3alpha4alpha5 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 alpha1alpha1 and/or alpha2alpha1 control mesangial collagen IV homeostasis. Project 3 will determine the structural basis whereby the transmembrane and cytoplasmic domains of integrin alpha1alpha1 and alpha2alpha1 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.