Ullrich Syndrome: Pathogenesis and Therapies

乌尔里希综合征：发病机制和治疗

• 批准号: 7022094
• 负责人: MON-LI H. CHU
• 金额: $ 34.28万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-21 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022094
• 关键词: adeno associated virus group; chemical stability; clinical research; collagen; congenital disorders; disease /disorder etiology; disease /disorder model; extracellular matrix; fibroblasts; gene expression; gene mutation; gene targeting; genetically modified animals; human subject; laboratory mouse; molecular pathology; musculoskeletal disorder; musculoskeletal disorder therapy; therapy design /development; transfection /expression vector; zebrafish

DESCRIPTION (provided by applicant): Ullrich syndrome is a severe congenital musculoskeletal disorder affecting multiple organ systems. The major clinical features include muscle weakness, proximal joint contractures, distal hyper extensibility, kyphoscoliosis, spine rigidity and skin abnormalities. In the severe presentation of the disease, independent walking is not achieved owing to progression of muscle weakness and contractures, and most patients die of respiratory failure during the first to third decades of life. The disease has recently been shown to result from recessive or dominant negative mutations of type VI collagen genes. Collagen VI forms a filamentous network widely distributed in most soft connective tissues and cartilage. It plays important roles in cell-matrix and matrix-matrix interactions, and changes in the expression and localization of collagen VI microfibrils are associated with common musculoskeletal diseases such as osteoarthritis. This application seeks to understand the pathogenesis of Ullrich syndrome and to develop therapies for this disabling and often fatal disease. Mouse models harboring targeted collagen VI mutations will be generated and the structural organization of the extracellular matrix in tendon, joint, muscle and skin will be analyzed to delineate the pathogenic mechanisms of disease progression. The biochemical basis of collagen VI microfibrillar assembly and the effects of disrupting microfibrillar formation during musculoskeletal development will be elucidated. In addition, therapeutic approaches for Ullrich syndrome resulting from recessive and dominant negative mutations will be explored. The proposed studies will lay the groundwork for future therapeutic intervention of genetic and acquired diseases associated with disorganization of collagen VI microfibrils.

描述（由申请人提供）：乌尔里希综合征是一种影响多个器官系统的严重先天性肌肉骨骼疾病。主要临床特征包括肌肉无力、近端关节挛缩、远端过度伸展、脊柱后凸、脊柱强直和皮肤异常。在疾病严重的情况下，由于肌肉无力和挛缩的进展，无法实现独立行走，并且大多数患者在生命的第一个到第三个十年期间死于呼吸衰竭。最近已证明该疾病是由 VI 型胶原蛋白基因的隐性或显性阴性突变引起的。 VI 型胶原蛋白形成丝状网络，广泛分布于大多数软结缔组织和软骨中。它在细胞-基质和基质-基质相互作用中发挥重要作用，VI 型胶原微纤维表达和定位的变化与骨关节炎等常见的肌肉骨骼疾病有关。该应用旨在了解乌尔里希综合征的发病机制，并开发针对这种致残且往往致命的疾病的疗法。将生成含有目标胶原 VI 突变的小鼠模型，并分析肌腱、关节、肌肉和皮肤中细胞外基质的结构组织，以描绘疾病进展的致病机制。将阐明 VI 型胶原蛋白微纤维组装的生化基础以及在肌肉骨骼发育过程中破坏微纤维形成的影响。此外，还将探索由隐性和显性阴性突变引起的乌尔里希综合征的治疗方法。拟议的研究将为未来与 VI 型胶原微原纤维破坏相关的遗传性疾病和获得性疾病的治疗干预奠定基础。