Ullrich Syndrome: Pathogenesis and Therapies

描述（由申请人提供）：Ullrich综合征是一种严重的先天性肌肉骨骼疾病，影响多个器官系统。主要临床特征包括肌无力、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。在病情严重的情况下，由于肌肉无力和挛缩的进展，无法独立行走，大多数患者在生命的第一至第三十年死于呼吸衰竭。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。胶原VI形成广泛分布于大多数软结缔组织和软骨中的丝状网络。它在细胞-基质和基质-基质相互作用中起重要作用，并且胶原VI微纤维的表达和定位的变化与常见的肌肉骨骼疾病如骨关节炎相关。本申请旨在了解Ullrich综合征的发病机制，并为这种致残且通常致命的疾病开发治疗方法。将生成携带靶向胶原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。VI型胶原微纤维组装的生化基础和肌肉骨骼发育过程中破坏微纤维形成的影响将得到阐明。此外，将探讨由隐性和显性阴性突变引起的Ullrich综合征的治疗方法。拟议的研究将奠定基础，为未来的治疗干预的遗传性和获得性疾病与VI型胶原微纤维的解体。

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.