PATHOLOGY OF INBORN SKELETAL DISEASES

先天骨骼疾病的病理学

• 批准号: 3158036
• 负责人: David R Eyre
• 金额: $ 21万
• 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 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3158036
• 关键词: Ehlers Danlos syndrome; Marfan syndrome; biological polymorphism; biopsy; cartilage; chondrodystrophy; collagen; collagen disorder; crosslink; electron microscopy; extracellular matrix; fibroblasts; gel electrophoresis; high performance liquid chromatography; histopathology; human population genetics; human subject; human tissue; mucopolysaccharidosis type IV; osteoarthritis; osteogenesis imperfecta; protein sequence; protein structure; protein structure function; tissue /cell culture

Inborn molecular defects in collagen structure are being characterized in various skeletal diseases. The emphasis is on osteogenesis imperfecta, Ehlers Danlos syndrome and certain chondrodystrophies. Of particular interest are diseases that result in structural mutations of collagen expressed in the extracellular matrix and their effects or collagen polymerization and cross-linking. The application of micro- techniques in protein chemistry to tissue biopsies is the theme of the work. The goal with osteogenesis imperfecta is to understand better how a diversity of mutatiotis in type I collagen all result in brittle bone. By studying bone tissue (surgery and autopsy) from patients of known molecular defect, the degree to which mutations are expressed and persist extracellularly in cross-linked bone matrix will be examined. Is the disease principally one of collagen underproduction rather than the consequences of structurally inadequate collagen molecules forming the matrix? Likewise, the consequences of structural mutations and post-translational defects of collagen in Ehlers-Danlos syndromes VI ind VII will be defined in more detail. Efforts will be made to reveal inherited structural defects in cartilage-specific collagens (types II and IX) as the cause of curtain forms of chondrodystrophy, including the broadly-defined spondyloepiphyseal dysplasias and diastrophic dysplasias. The possibility that polymorphisms of the human type II collagen gene exist in the population, and perhaps account for observed natural variations in degree of cross-linking in human cartilage collagen, will be tested. Inherited mutations of type II collagen affecting cross-linking as a cause of familial osteoarthrosis will also be examined. The objective is to learn the importance of certain features of collagen structure, for example those that control cross-linking reactions, in determining function. Through an understanding of the effects of rare inborn mutations, so the normal properties of collagens and their variations can be better appreciated.

胶原蛋白结构中的先天分子缺陷正在被表征 在各种骨骼疾病中。重点是成骨 不完美症、埃勒斯·丹洛斯综合征和某些软骨营养不良症。的 特别感兴趣的是导致结构突变的疾病 细胞外基质中表达的胶原蛋白及其作用或 胶原蛋白聚合和交联。微机电的应用 蛋白质化学技术到组织活检是本次会议的主题 工作。 成骨不全症的目标是更好地了解成骨不全症如何 I型胶原蛋白突变的多样性都会导致骨质脆化。 通过研究已知患者的骨组织（手术和尸检） 分子缺陷，突变表达的程度以及 将检查细胞外在交联骨基质中的持续存在。是 这种疾病主要是胶原蛋白生成不足，而不是 结构上不足的胶原蛋白分子形成的后果 矩阵？同样，结构突变的后果和 埃勒斯-当洛斯综合征 VI 中胶原蛋白翻译后缺陷 VII将被更详细地定义。 将努力揭示遗传性结构缺陷 软骨特异性胶原蛋白（II 型和 IX 型）作为幕帘的原因 软骨营养不良的各种形式，包括广义的 脊柱骨骺发育不良和破坏性发育不良。这 人类II型胶原蛋白基因多态性存在的可能性 在人群中，也许可以解释观察到的自然变化 将测试人类软骨胶原蛋白的交联程度。 II 型胶原蛋白的遗传突变影响交联 还将检查家族性骨关节病的原因。 目的是了解胶原蛋白某些特征的重要性 结构，例如控制交联反应的结构， 确定函数。通过了解稀有物质的影响 先天突变，因此胶原蛋白的正常特性及其 可以更好地理解变化。