Collagen Glomerulopathy: COL1A2 Deficient Mouse Model

描述（由申请人提供）：慢性肾脏疾病中，胶原蛋白在肾小球系膜基质中的进行性积累是一个主要的病理结果，最终导致肾小球硬化和肾衰竭。过量的细胞外基质（ECM）的产生被认为是由于肾小球伤口愈合反应的过度代偿。虽然我们对导致ECM积累的起始事件了解甚多，但对ECM在肾小球系膜细胞反应发病机制中的作用知之甚少。最近，我们在proa2(1)胶原蛋白缺乏小鼠（oim）中发现了一种新的胶原蛋白肾小球病变，这有望为I型胶原蛋白在肾小球疾病发病机制中的调节作用提供新的见解。Oim/ Oim小鼠（COL1A2基因纯合子零）的独特之处在于它们只能合成同型三聚体I型胶原a1(l)3，而不能合成正常的异源三聚体I型胶原a1(l)2a2(l)。缺乏a2(l)胶原链可导致肾小球系膜内同质三聚体I型胶原沉积。与正常的健康肾脏肾小球中不存在I型胶原相比，胶原沉积和肾小球扩张是导致肾脏疾病进展和衰竭的共同特征，提示三聚体I型胶原可能在肾小球硬化的发病机制中发挥重要作用。我们的长期目标是了解参与肾小球硬化的ECM沉积和发病机制的分子机制，以便确定治疗干预的靶点。为此，我们建议：1)表征oim/oim小鼠I型胶原肾小球病变的自然进展，并将病理结果与疾病进展联系起来；2)从机制上确定I型胶原沉积在oim/oim肾小球中是胶原表达增加还是基质降解异常的结果；3)确定基质金属蛋白酶是否会以不同的方式切割同型三聚体和异型三聚体I型胶原。

DESCRIPTION (provided by applicant): In chronic renal disease the progressive accumulation of collagen in the glomerular mesangial matrix is a major pathological consequence, culminating in glomerulosclerosis, and renal failure. The production of excess extracellular matrix (ECM) is hypothesized to result from over compensation of the glomerular wound healing response. Though much is known concerning the initiating events leading to accumulation of the ECM, very little is known mechanistically about the role of the ECM in the pathogenesis of the glomerular mesangial cell response. Recently, we identified a novel collagen glomerulopathy in a proa2(l)collagen deficient mouse (oim), which promises to provide new insight into the regulatory role of type I collagen in the pathogenesis of glomerular disease. Oim/oim mice (homozygous null for the COL1A2 gene) are unique in that they exclusively synthesize homotrimeric type I collagen, a1(l)3, and are unable to synthesize normal heterotrimeric type I collagen, a1(l)2a2(l). Lacking a2(l) collagen chains results in deposition of homotrimeric type I collagen in the glomerular mesangium. In contrast to intact healthy kidney where no type I collagen is normally present in the glomeruli, collagen deposition and glomerular expansion are common features contributing to progressive renal disease and failure, suggesting that homotrimeric type I collagen may play an important role in the pathogenesis of glomerulosclerosis. Our long term goal is to understand the molecular mechanisms involved in the ECM deposition and pathogenesis of glomerulosclerosis in order to identify targets for therapeutic interventions. Towards this end we propose to 1) characterize the natural progression of the collagen type I glomerulopathy in oim/oim mice and to correlate pathological findings with disease progression, 2) to determine mechanistically whether type I collagen deposition in the oim/oim glomeruli is a consequence of increased collagen expression or aberrant matrix degradation, and 3) to determine if matrix metalloproteinases differentially cleave homotrimeric and heterotrimeric type I collagen.