Biglycan as a Therapeutic for Muscular Dystrophy

描述(由申请人提供)：这项提案的总体目标是使用动物模型来测试Biglycan作为一种蛋白质治疗肌营养不良症的疗效。杜兴氏肌营养不良症(DMD)是一种遗传性疾病，大约每3500名男孩中就有一人受到影响。这些孩子通常在12岁时就必须坐在轮椅上，很少能活到20岁出头。目前还没有有效的治疗方法来治疗DM0的基本病理。Duchenne‘s和许多其他肌营养不良症的分子发病机制被追溯到肌肉细胞表面的一种特殊的蛋白质集合，称为dystrophin相关蛋白复合体(DAPC)。抗肌营养不良蛋白的突变导致DAPC的组织中断。DAPC功能的丧失会导致肌肉细胞的损伤和丧失。我们最近发现，细胞外基质分子Biglycan在肌肉细胞表面表达，并以不同的机制与DAPC的三个核心成分的胞外结构域结合：α-肌营养不良聚糖、α-肌聚糖和γ-肌聚糖。这些分子相互作用表明，Biglycan可以连接DAPC的组成亚复合体，从而从细胞外协调和稳定整个复合体。事实上，Biglycan Null(BGN-/o)小鼠表现出营养不良的表型，表现为肌肉细胞膜变弱和细胞死亡。这些观察表明，当Dystrophin缺失时，Biglycan可以起到治疗的作用，从细胞外的角度稳定DAPC。因此，Biglycan代表了一条开发肌肉营养不良疗法的新途径。重要的是，由于Biglycan-DAPC的相互作用完全是细胞外的，所以Biglycan可以通过系统地输送纯化的重组蛋白进入肌肉。该计划将利用独特的生产方法生产足够数量的高质量Biglycan，并在几种肌营养不良症动物模型上测试疗效。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to use animal models to test the efficacy of biglycan as a protein therapeutic for muscular dystrophy. Duchenne's muscular dystrophy (DMD) is a heritable disease that affects approximately 1 in 3,500 boys. These children are usually wheelchair-bound by age 12 and rarely survive past their early twenties. There are currently no effective treatments for the underlying pathology of DM0. The molecular pathogenesis of Duchenne's and many other muscular dystrophies has been traced to a specialized ensemble of proteins at the muscle cell surface known as the dystrophin-associated protein complex (DAPC). Mutation of dystrophin leads to disruption in the organization of the DAPC. The resulting failure of DAPC function results in muscle cell damage and loss. We have recently discovered that the extracellular matrix molecule biglycan is expressed at the muscle cell surface and binds, by distinct mechanisms, to the ectodomains of three core constituents of the DAPC: alpha-dystroglycan, aipha-sarcoglycan and gamma-sarcoglycan. These molecular interactions indicate that biglycan can bridge the component subcomplexes of the DAPC and thus coordinate and stabilize the entire complex from outside the cell. Indeed, biglycan null (bgn-/o) mice display a dystrophic phenotype as evidenced by weakened muscle cell membranes and cell death. These observations suggest that biglycan could serve as a therapeutic to stabilize the DAPC from its extracellular aspect when dystrophin is absent. Biglycan thus represents a new path for developing therapies for muscular dystrophies. Importantly, since the biglycan-DAPC interactions are wholly extracellular, biglycan can be introduced to the muscle by systemic delivery of the purified recombinant protein. This program will utilize unique production methods to produce sufficient quantities of high quality biglycan, .and test efficacy in several animal models of muscular dystrophy.