HERITABLE DISORDERS OF CONNECTIVE TISSUE

遗传性结缔组织疾病

• 批准号: 3756652
• 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/3756652
• 关键词: Ehlers Danlos syndrome; alleles; antisense nucleic acid; bone density; child (0-11); child physical development; clinical trials; collagen disorder; gene mutation; genetic disorder; genetic markers; hormone therapy; human subject; human therapy evaluation; human tissue; interview; molecular pathology; osteoblasts; osteogenesis imperfecta; somatotropin; tissue /cell culture

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 (EDS), and at applying this information to the treatment of these disorders. One primary interest of the Section is to identify the collagen mutations in patients with OI and EDS and determine the relationship between the type and location of the mutation and the severity of the connective tissue disorder. Mutations in the alpha2(I) collagen chain identified by this Section and other labs have provided additional support for the regional model we have proposed. A second primary interest of the Section is to develop selective antisense suppression of the mutant collagen allele as an approach for therapeutic intervention. We have used thio oligos targeted to mutant mRNA nd nuclear RNA in the cultured fibroblasts of a patient with type IV OI. We have achieved selective suppression of the mutant allele and are pursuing approaches such as ribozymes and vector constructs to increase suppression efficiency. A third focus of interest which we have been developing is in the bone biology of OI. We are using cultured osteoblasts to study the way bone cells modify and secrete mutant collagen. We are also pursing the secondary non-collagenous abnormalities of OI matrix. In clinical studies, we are continuing our treatment trial of growth hormone in short children with OI to determine its effects on growth stimulation, bone density and bone morphometric properties. We are continuing our collaborative interests in the neurological aspects of OI and in maximizing the physical functioning of OI children though aggressive rehabilitation.

该科继续进行研究， 结缔组织遗传性疾病的机制，特别是 成骨诱导因子（OI）和Ehlers-Danlos（EDS）， 这些信息对这些疾病的治疗。 本节的一个主要目的是确定胶原突变 在OI和EDS患者中， 突变的类型和位置以及结缔组织的严重程度 组织紊乱α 2（I）胶原蛋白链中的突变， 本节和其他实验为 我们提出的区域模型。 该科的第二个主要兴趣是制定有选择的 反义抑制突变胶原等位基因作为一种方法 治疗干预我们使用硫代寡核苷酸靶向 突变mRNA 在培养的成纤维细胞中， IV型OI。我们已经实现了对突变等位基因的选择性抑制 并正在寻求诸如核酶和载体构建体的方法， 提高了抑制效率。 我们一直在研究的第三个关注点是骨骼 生物学Oi我们用培养的成骨细胞来研究骨骼 细胞修饰并分泌突变胶原。我们也在追求 OI基质的继发性非胶原异常。 在临床研究中，我们正在继续我们的治疗试验的增长 激素对发育不全矮小儿童生长影响 刺激、骨密度和骨形态测量特性。我们 继续我们在OI神经方面的合作兴趣 最大限度地发挥OI儿童的身体功能， 积极的康复