Collagen Glomerulopathy: COL1A2 Deficient Mouse Model

胶原蛋白肾小球病：COL1A2 缺陷小鼠模型

• 批准号: 7229786
• 负责人: CHARLOTTE L PHILLIPS
• 金额: $ 14.27万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229786
• 关键词: Affect; Age; Age-Months; Biological Assay; Blood Urea Nitrogen; COL1A2 gene; Chronic Kidney Failure; Cleaved cell; Collagen; Collagen Gene; Collagen Type I; Creatinine; Deposition; Disease; Disease Progression; Event; Excretory function; Extracellular Matrix; Failure; Fibrosis; Financial compensation; Formalin; Gel; Gelatinase A; Gelatinase B; Genotype; Glomerular Mesangial Cell; Goals; Histologic; In Situ; In Situ Hybridization; In Vitro; Interstitial Collagenase; Kidney; Kidney Diseases; Kidney Failure; Matrix Metalloproteinases; Molecular; Mus; Neutrophil Collagenase; Numbers; Pathogenesis; Play; Production; Proteins; Rate; Renal function; Renal glomerular disease; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Serum; Severities; Specificity; Stromelysin 1; Structure of glomerular mesangium; Therapeutic Intervention; Wound Healing; alpha 2 collagen type I; collagenase 3; day; glomerulosclerosis; insight; mouse model; novel; programs; response; urinary

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.

描述（由申请人提供）：在慢性肾脏疾病中，肾小球系膜基质中胶原蛋白的进行性积累是一种主要的病理后果，最终导致肾小球硬化和肾衰竭。过量细胞外基质（ECM）的产生被假设是由于肾小球伤口愈合反应的过度补偿。虽然知道很多关于启动事件导致积累的ECM，很少有人知道的机制ECM的作用，在肾小球系膜细胞反应的发病机制。最近，我们在proa 2（l）胶原蛋白缺陷小鼠（oim）中发现了一种新的胶原蛋白肾小球病，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（COL 1A 2基因的纯合无效）是独特的，因为它们仅合成纯三聚体I型胶原，a1（l）3，并且不能合成正常的异三聚体I型胶原，a1（l）2a 2（l）。缺乏α 2（I）胶原蛋白链导致同源三聚体I型胶原蛋白在肾小球系膜中沉积。与正常情况下肾小球中不存在I型胶原的完整健康肾脏相反，胶原沉积和肾小球扩张是导致进行性肾病和肾衰竭的常见特征，这表明同源三聚体I型胶原可能在肾小球硬化症的发病机制中起重要作用。我们的长期目标是了解ECM沉积和肾小球硬化症发病机制的分子机制，以确定治疗干预的目标。为此，我们提出1）表征oim/oim小鼠中I型胶原肾小球病的自然进展，并将病理学发现与疾病进展相关联，2）从机理上确定oim/oim肾小球中的I型胶原沉积是否是胶原表达增加或异常基质降解的结果，和3）确定基质金属蛋白酶是否有区别地切割同源三聚体和异源三聚体I型胶原。

项目成果

Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion.

• DOI: 10.1158/0008-5472.can-09-4057
• 发表时间: 2010-06-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Makareeva E;Han S;Vera JC;Sackett DL;Holmbeck K;Phillips CL;Visse R;Nagase H;Leikin S
• 通讯作者: Leikin S