Ullrich Syndrome: Pathogenesis and Therapies

描述（由申请人提供）：乌尔里希综合征是一种影响多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、脊柱僵硬和皮肤异常。在病情严重的情况下，由于肌肉无力和挛缩的进展，无法实现独立行走，大多数患者在生命的第一个到第三个十年死于呼吸衰竭。该疾病最近被证明是由VI型胶原基因的隐性或显性负突变引起的。VI型胶原形成丝状网络，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-基质相互作用中起重要作用，胶原VI微原纤维的表达和定位变化与骨关节炎等常见肌肉骨骼疾病有关。该应用程序旨在了解乌尔里希综合征的发病机制，并为这种致残且往往致命的疾病开发治疗方法。将生成含有靶向胶原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，以描述疾病进展的致病机制。将阐明胶原VI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，对隐性和显性负突变导致的乌尔里希综合征的治疗方法将进行探讨。所提出的研究将为未来与胶原VI微原纤维紊乱相关的遗传和获得性疾病的治疗干预奠定基础。

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.