PATHOBIOLOGY OF INBORN SKELETAL DISEASES

先天性骨骼疾病的病理学

• 批准号: 3158035
• 负责人: David R Eyre
• 金额: $ 15.52万
• 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 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3158035
• 关键词: Ehlers Danlos syndrome; Marfan syndrome; cartilage; chondrodystrophy; collagen; collagen disorder; crosslink; electron microscopy; fibroblasts; gel electrophoresis; high performance liquid chromatography; human subject; messenger RNA; mucopolysaccharidosis type IV; osteogenesis imperfecta; procollagen; protein sequence; protein structure; tissue /cell culture

Underlying structural defects of collagen are being sought in human connective tissues diseases. Of particular interest are those inborn disorders that affect the musculoskeleton, the more common ones being the Ehlers-Danlos syndromes, osteogenesis imperfecta, and Marfan's syndrome. A rich source of such rare tissues is available to us here and through collaborative contacts. Our primary approach is direct analysis of tissue matrix collagens by biochemical techniques. A portion of effort is spent screening promising new cases, but the main effort is devoted to follow-up studies in depth on identified collagen mutants. Though collagen disorders are the prime target, signs of proteoglycan defects would be pursued. A major goal is to gain unique insights on the relationship between structure and function of collagen, as well as helping detect, treat and prevent these skeletal disorders. Collagen cross-linking receives keen attention since cross-linking defects are common to many of the known diseases of the collagen molecule, and seems a good index of structural integrity. Techniques include slabgel electrophoresis and reverse phase HPLC chromatography of collagen polypeptides and derived fragments, and electronmicroscopy of collagen fibrils and cells in affected tissues. Where appropriate skin fibroblasts will be grown to characterize procollagen products. Appropriate tissue specimens will be frozen for future DNA and RNA analyses by collaborators should defects be indicated at the protein level. Specific cases for follow-up identified in the last two years by tissue screening include: 1) a new case of EDS VII in which a short deletion spanning the Alpha2(I)-chain amino-telopeptide domain is indicated; 2) a new case of EDS VI with no hydroxylysine in skin and lysyl pyridinoline replacing hydroxylysyl pyridinoline cross-links in cartilage; 3) two lethal newborn cases of spondylepiphyseal dysplasia in which a structural mutation of Alpha1(II) is present; 4) achondrogenesis type II (Langer-Saldino) that totally lacks type II collagen in cartilage; and 5) bone from several cases of osteogenesis imperfecta. In addition we will screen for cross-linking abnormalities in aortic collagen of Marfan's patients. Inborn disorders that impair the structure and development of the skeleton account for a significant fraction of the 12 million Americans who have birth defects. Collagen abnormalities will account for a significant number of these.

人类正在寻找胶原蛋白的潜在结构缺陷 结缔组织疾病。 特别令人感兴趣的是那些天生的 影响肌肉骨骼的疾病，最常见的是 埃勒斯-当洛斯综合征、成骨不全症和马凡氏综合征。 一个 我们可以在这里和通过以下渠道获得此类稀有组织的丰富来源 协作联系。 我们的主要方法是直接分析组织 通过生化技术制备基质胶原蛋白。 花费了一部分精力 筛选有希望的新病例，但主要精力放在后续工作上 对已识别的胶原蛋白突变体进行深入研究。 虽然胶原蛋白紊乱 是主要目标，将追踪蛋白多糖缺陷的迹象。 一个 主要目标是获得对结构之间关系的独特见解 和胶原蛋白的功能，以及帮助检测、治疗和预防 这些骨骼疾病。 胶原蛋白交联受到广泛关注 因为交联缺陷对于许多已知的疾病来说是常见的 胶原蛋白分子，似乎是结构完整性的良好指标。 技术包括平板凝胶电泳和反相 HPLC 胶原蛋白多肽和衍生片段的色谱分析，以及 受影响组织中胶原纤维和细胞的电子显微镜检查。 在适当的情况下，将培养皮肤成纤维细胞来表征 前胶原蛋白产品。 适当的组织标本将被冷冻保存 合作者未来进行的 DNA 和 RNA 分析应在以下位置指出缺陷： 蛋白质水平。 近两年组织发现的具体随访案例 筛选包括：1）一个新的 EDS VII 病例，其中有一个短缺失 显示了跨越 Alpha2(I)-链氨基端肽结构域； 2）一个 新病例 EDS VI 皮肤中不含羟赖氨酸和赖氨酰吡啶啉 取代软骨中的羟赖氨酰吡啶啉交联； 3）两次致命 脊柱骨骺发育不良的新生儿病例，其中结构突变 Alpha1(II) 存在； 4) II 型软骨发育不全 (Langer-Saldino) 软骨中完全缺乏II型胶原蛋白； 5）来自多个病例的骨头 成骨不全症。 此外，我们还将筛选交联 马凡氏病患者主动脉胶原蛋白异常。 损害骨骼结构和发育的先天性疾病 占 1200 万美国人中的很大一部分 出生缺陷。 胶原蛋白异常将造成重大影响 这些的数量。