HERITABLE DISORDERS OF CONNECTIVE TISSUE

遗传性结缔组织疾病

• 批准号: 3857088
• 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/3857088
• 关键词: Ehlers Danlos syndrome; autoimmune disorder; autosomal dominant trait; child (0-11); clinical trials; collagen; connective tissue development; connective tissue disorder; connective tissue disorder chemotherapy; family; fibroblasts; genetic disorder; heterozygote; human subject; human therapy evaluation; human tissue; molecular genetics; molecular pathology; nucleic acid hybridization; nucleic acid probes; osteogenesis imperfecta; pathologic ossification; point mutation; postnatal growth disorder; protein biosynthesis; protein structure; thermostability; vasculitis

We have continued our studies to elucidate the molecular mechanisms of heritable disorders of connective tissue, specifically osteogenesis imperfecta and Ehlers-Danlos syndrome, and to apply this information to the treatment of these disorders. We have applied our collagen protein analysis and RNA hybrid methodology to (1) two moderately severe cases of OI, in both of which we delineated substitutions of serine for glycine. One mutation is at alpha-1(I) gly 352; This is the predominant alpha-1(I) chain made by the proband because the normal allele has reduced transcription. The other mutation is at alpha-2(I) gly 922 and causes reduced thermal stability of the collagen helix; in this case, the proband's unaffected father was shown to be a mosaic for the mutation and at risk of producing further affected offspring. (2) Cases with variability of expression, compound heterozygosity or germ line mosaicism to explore the molecular basis of variable expression in a dominant disorder of structural protein. (3) Cases of Ehlers-Danlos syndrome with evidence of a type I collagen abnormality. We have also demonstrated a type I collagen abnormality in a case of EDS with autoimmune vasculitis and a collagen-specific immunoprotein. In clinical protocols, we have continued our investigation of growth deficiency in OI and are about to initiate a full-scale treatment trial. The collaborative cross-over bracing protocol for weaning of braces has concluded Phase 1 and crossed-over.

我们继续我们的研究，以阐明分子机制， 结缔组织遗传性疾病，特别是骨生成 Ehlers-Danlos综合征，并将此信息应用于 治疗这些疾病。 我们已经将我们的胶原蛋白分析和RNA杂交方法应用于 (1)两个中度严重的OI病例，在这两个病例中， 丝氨酸取代甘氨酸。 一个突变发生在α-1（I）Gly 352;这是先证者产生的主要α-1（I）链，因为 正常等位基因的转录减少。 另一个突变发生在 α-2（I）gly 922并导致胶原蛋白的热稳定性降低 螺旋;在这种情况下，先证者的未受影响的父亲被证明是一个 嵌合体的突变和风险产生进一步影响 后代 (2)具有表达变异性、复合杂合性或胚性的病例 线镶嵌来探索细胞中可变表达的分子基础 结构蛋白显性障碍 (3)有I型胶原证据的Ehlers-Danlos综合征病例 异常 我们还证明了在一个有着广泛的临床意义的人中I型胶原蛋白异常。 EDS伴自身免疫性血管炎和胶原特异性 免疫蛋白 在临床方案中，我们继续研究生长 缺乏OI，并即将启动全面的治疗试验。 协作交叉支撑协议，为断奶的括号， 第1阶段结束并交叉。