Collagen Glomerulopathy: COL1A2 Deficient Mouse Model

描述(申请人提供)：在慢性肾脏疾病中，肾小球系膜基质中胶原的进行性积聚是一个主要的病理后果，最终导致肾小球硬化和肾功能衰竭。过量细胞外基质(ECM)的产生被认为是肾小球创伤修复反应过度代偿的结果。虽然对导致ECM积聚的起始事件已知很多，但从机制上对ECM在肾小球系膜细胞反应中的作用知之甚少。最近，我们在一只ProA2(L)胶原缺乏症小鼠身上发现了一种新的胶原肾小球病变，这有望为I型胶原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基因纯合缺失)的独特之处在于它们只合成I型胶原同源三聚体A1(L)3，而不能合成正常的异三聚I型胶原A1(L)2A2(L)。缺乏a2(L)胶原链导致肾小球系膜内同源三聚体I型胶原沉积。与正常肾小球中不存在I型胶原的完整健康肾脏不同，胶原沉积和肾小球扩张是导致进展性肾脏疾病和肾功能衰竭的共同特征，提示同源三聚体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ECM沉积和肾小球硬化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)描述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OIM/OIM肾小球中I型胶原沉积是胶原表达增加还是异常基质降解的结果；以及3)确定基质金属蛋白酶是否对同型和异型三聚体I型胶原有不同的裂解作用。

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.