PATHOLOGY OF INBORN SKELETAL DISEASES

先天性骨骼疾病的病理学

• 批准号: 6532941
• 负责人: David R Eyre
• 金额: $ 28.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532941
• 关键词: articular cartilage; biopsy; chondrocytes; chondrodystrophy; clinical research; collagen; collagen disorder; collagenase; congenital skeletal disorder; crosslink; extracellular matrix; family genetics; gene mutation; genetic polymorphism; high performance liquid chromatography; histopathology; human subject; human tissue; molecular pathology; osteoarthritis; protein isoforms; protein structure function; proteolysis; tissue /cell culture

The topic is basic research on the molecular effects of mutations that affect collagens and other extracellular proteins and cause heritable skeletal disorders. A key goal is to understand molecular events in articular cartilage that predispose to and accompany joint degeneration. The focus is on cartilage collagens, in particular the heteropolymeric assemblage of collagen types II, IX and XI and their associated matrix molecules. By studying structural changes at the protein level and their potential to affect the susceptibility of fibrils to proteolysis, the knowledge gap on how such gene defects translate into tissue pathogenesis and clinical disease is being addressed. As molecular techniques rapidly uncover mutations and polymorphisms that cause or predispose to skeletal disorders, there is a growing need to know that mechanisms of disease pathogenesis. Here, the approach is to study the protein defects in tissues obtained at surgery or autopsy from heritable chondrodysplasias that affect cartilage matrix structure. They include Kniest dysplasia, a severe disorder caused by COL2A1 (collagen II) mutations; multiple epiphyseal dysplasia (MED), a mild-to-moderate skeletal dysplasia with early-onset osteoarthritis of knees and hips, caused by collagen IX or COMP mutations; familial osteoarthritis, with or without mild spondyloepiphyseal dysplasia (SED) caused by COL2A1 mutations or mutations in collagens IX and XI genes. Molecular reasons for the predisposition to joint degeneration in these conditions are being sought. A hypothesis that mutant allelic products are deposited in extracellular fibrils and promote damage by proteases normally incapable of attacking fibrils, is being tested. Collagen type II, III, IX and XI degradation products are being compared in heritable disease to those generated in normal cartilage and in joints affected by acquired OA. The growing number of reports of mutations in collagen genes that predispose to premature joint failure (synovial and intervertebral joints) drive the direction of this research. By defining molecular mechanisms whereby genetic factors cause joints to fail leads on novel therapeutic and preventive measures are anticipated.

该主题是关于影响胶原蛋白和其他细胞外蛋白并导致遗传性骨骼疾病的突变的分子效应的基础研究。 一个关键目标是了解关节软骨中易于发生并伴随关节退化的分子事件。 重点是软骨胶原蛋白，特别是 II、IX 和 XI 型胶原蛋白的异聚物及其相关基质分子。 通过研究蛋白质水平的结构变化及其影响原纤维对蛋白水解的敏感性的潜力，正在解决此类基因缺陷如何转化为组织发病机制和临床疾病的知识差距。随着分子技术迅速发现导致或诱发骨骼疾病的突变和多态性，人们越来越需要了解疾病的发病机制。 在这里，该方法是研究在手术或尸检中从影响软骨基质结构的遗传性软骨发育不良中获得的组织中的蛋白质缺陷。 其中包括 Kniest 发育不良，这是一种由 COL2A1（II 型胶原蛋白）突变引起的严重疾病；多发性骨骺发育不良 (MED)，一种轻至中度骨骼发育不良，伴有膝部和髋部早发性骨关节炎，由 IX 型胶原蛋白或 COMP 突变引起；家族性骨关节炎，伴有或不伴有由 COL2A1 突变或胶原蛋白 IX 和 XI 基因突变引起的轻度脊椎骨骺发育不良 (SED)。 正在寻找这些条件下关节退化倾向的分子原因。 突变等位基因产物沉积在细胞外原纤维中并促进通常无法攻击原纤维的蛋白酶造成的损伤的假设正在接受测试。 正在将遗传性疾病中的 II、III、IX 和 XI 型胶原蛋白降解产物与正常软骨和受获得性 OA 影响的关节中产生的降解产物进行比较。 越来越多的关于胶原蛋白基因突变导致关节过早衰竭（滑膜和椎间关节）的报道推动了这项研究的方向。 通过定义遗传因素导致关节衰竭的分子机制，预计可以找到新的治疗和预防措施。