HERITABLE DISORDERS OF CONNECTIVE TISSUE

遗传性结缔组织疾病

• 批准号: 5203304
• 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/5203304
• 关键词: Ehlers Danlos syndrome; alleles; antisense nucleic acid; bone density; child (0-11); child physical development; clinical trials; collagen disorder; connective tissue disorder chemotherapy; gene mutation; genetic disorder; genetic markers; hormone therapy; human genetic material tag; 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 `2(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 and nuclear RNA in the cultured fibroblasts of a patient with type IV OI. More recently, we have successfully used ribozymes in vitro to obtain allele-specific cleavage and are now pursuing vector constructs to increase suppression stability and 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.

该科继续进行旨在阐明分子的研究。 结缔组织遗传性疾病的机制，特别是 成骨不全(OI)和Ehler-Danlos(EDS)及其应用 这一信息有助于这些疾病的治疗。 该部分的一个主要兴趣是确定胶原突变 在OI和EDS患者中并确定两者之间的关系 突变的类型和位置以及连接的严重程度 组织紊乱。由此确定的`2(I)胶原链的突变 部门和其他实验室为地区性的 我们提出的模型。 该科的第二个主要兴趣是制定有选择性的 反义抑制突变的胶原等位基因作为一种治疗方法 治疗性干预。我们已经使用了针对突变体的硫代寡聚糖 一例类风湿关节炎患者培养成纤维细胞中的mRNA和核RNA 静脉输液。最近，我们成功地在体外使用核酶 获得等位基因特异的切割，现在正在研究载体构建 以增加压制的稳定性和效率。 我们一直在开发的第三个兴趣焦点是骨骼 OI的生物学。我们正在使用培养的成骨细胞来研究骨骼的方式 细胞修饰和分泌突变的胶原蛋白。我们还在追求 继发性OI基质非胶原性异常。 在临床研究中，我们正在继续我们的生长治疗试验。 OI矮小儿童体内激素对生长发育的影响 刺激、骨密度和骨形态计量学特性。我们是 继续我们在OI的神经学方面的合作兴趣 在最大化OI儿童的身体功能方面， 积极的康复。