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.

该主题是对影响胶原蛋白和其他细胞外蛋白的突变的分子效应的基础研究，并引起可遗传的骨骼疾病。 一个关键目标是了解易感和伴随关节变性的关节软骨中的分子事件。 重点是软骨胶原蛋白，尤其是胶原蛋白II型，IX和XI及其相关基质分子的异质质组合。 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，关于这种基因缺陷如何转化为组织发病机理和临床疾病的知识差距。由于分子技术迅速发现引起或易感骨骼疾病的突变和多态性，因此越来越需要知道疾病发病机理的机理。 在这里，这种方法是研究在手术中获得的组织中的蛋白质缺陷或影响软骨基质结构的可遗传软骨发育不良的尸检。 它们包括由COL2A1（胶原II）突变引起的严重疾病的膝盖发育不全；多发性骨膜发育不良（MED）是一种轻度至中度的骨骼发育不良，膝盖和臀部早期发作的骨关节炎，由胶原蛋白IX或COMP突变引起；家族性骨关节炎，有或没有轻度的脊椎骨腺骨膜造成障碍（SED），由Col2A1突变或突变引起的胶原IX和XI基因引起。 在寻求这些条件下关节变性的分子原因正在寻求。 一个假说，即突变等位基因产物沉积在细胞外纤维中，并促进通常无法攻击原纤维的蛋白酶的损害。 将胶原蛋白II，III，IX和XI降解产物与正常软骨和受到获得的OA影响的关节进行了比较。 在胶原蛋白基因中的突变报告越来越多，易于过早的关节失败（滑膜和椎间关节）驱动了这项研究的方向。 通过定义分子机制，遗传因素会导致关节在新型治疗和预防措施上导致关节失败。