HERITABLE DISORDERS OF CONNECTIVE TISSUE

遗传性结缔组织疾病

• 批准号: 3842285
• 负责人: J C MARINI
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3842285
• 关键词: Ehlers Danlos syndrome; assistive device /technology; bone density; child (0-11); child physical development; clinical trials; collagen; genetic disorder; genetic markers; human subject; human therapy evaluation; human tissue; molecular pathology; osteogenesis imperfecta; point mutation; postnatal growth disorder; somatotropin

The section has continued its studies aimed at elucidating the molecular mechanisms of heritable disorders of connective tissue, specifically osteogenesis imperfecta OI) and Ehlers-Danlos syndrome (EDS), and to apply this information to the treatment of these disorders. One of the primary goals of the Section is to determine the relationship between the type and location of the type I collagen mutation and the severity of the bone disease. To this end, we have applied our collagen protein and RNA hybrid methodology to four cases of OI with a range of severities. We have demonstrated serine for glycine substitutions at different positions along the two collagen chains. We have proposed a regional model of OI pathophysiology in which there is an alternation along the chains of clusters of lethal and non-lethal mutations. In this model, the functional significance of the regions resides in higher order fibrils, secondary effects on osteoblast metabolism or interactions with no-collagenous matrix molecules. We have studied seven cases of mild-moderate EDS, and find that the collagen results in these cases converge with the OI studies. That is, the EDS cases have abnormalities of collagen protein similar to OI cases. Since the symptoms of EDS and OI overlap, except that EDS patients do not have brittle bone disease and osteoporosis, these cases provide important insight into regions of collagen which are non-crucial for bone structure. We are pursuing the molecular description of these cases using SSCP analysis. In clinical studies, we initiated a treatment trial of growth hormone in short children with OI and will determine its effects on linear growth, bone density and bone morphometric properties. We are concluding a collaborative cross-over protocol for weaning OI children from braces. We are exploring new carbon and polymer rodding materials.

该科继续进行研究，旨在阐明 结缔组织遗传性疾病的机制，特别是 成骨不全OI）和Ehlers-Danlos综合征（EDS），以及 将这些信息应用于这些疾病的治疗。 该科的主要目标之一是确定 I型胶原突变的类型和位置与 骨疾病的严重程度。为此，我们将胶原蛋白 蛋白质和RNA杂交方法对4例OI进行了检测， 严重性我们已经证明丝氨酸取代甘氨酸， 沿着两条胶原蛋白链的沿着不同位置。我们提出了一种 OI病理生理学的区域模型，其中存在交替 沿着致命和非致命突变的链。在这 模型，区域的功能意义在于更高的 顺序原纤维，对成骨细胞代谢的次要影响，或 与非胶原基质分子的相互作用。 我们研究了7例轻中度EDS，发现 这些病例中的胶原结果与OI研究一致。也就是说， EDS患者存在与OI相似的胶原蛋白异常 例由于EDS和OI的症状重叠，除了EDS 患者没有脆骨病和骨质疏松症，这些病例 提供了对胶原蛋白非关键区域的重要见解， 骨骼结构。我们正在研究这些分子的描述 SSCP分析。 在临床研究中，我们启动了一项生长激素治疗试验， 短的儿童与OI，并将确定其对线性增长的影响， 骨密度和骨形态测量特性。我们得出结论， 协作交叉协议，用于使OI儿童脱离支架。 我们正在探索新的碳和聚合物杆材料。