Signalling via Dystrobrevin in Muscular Dystrophy

肌营养不良蛋白复合物在维持肌肉健康方面的一个主要功能是在收缩期间为肌膜提供机械稳定性。然而，新出现的证据支持肌营养不良蛋白复合物的信号和/或支架功能，这为治疗方法提供了新的可能性。肌萎缩症中信号机制参与的最令人信服的证据可能来自α -肌营养不良蛋白缺失的小鼠，它发展为肌萎缩症。与缺乏营养不良蛋白的mdx小鼠不同，缺乏α -营养不良蛋白的小鼠几乎没有表现出任何肌层不稳定的迹象，这是染料摄取研究得出的结论。为了了解α -肌营养不良蛋白异常导致肌肉营养不良的机制，我们将确定α -肌营养不良蛋白的结构域

A major function of the dystrophin complex in maintaining muscle health is to provide mechanical stability to the sarcolemma during contraction. Emerging evidence, however, supports a signaling and/or scaffolding function for the dystrophin complex, which suggests new possibilities for therapeutic approaches. Perhaps the most convincing evidence for the involvement of a signaling mechanism in muscular dystrophy comes from the alpha-dystrobrevin null mouse which develops muscular dystrophy. Unlike its dystrophin null counterpart, the mdx mouse, the alpha-dystrobrevin null mouse shows little if any sign of sarcolemmal instability, as judged by dye uptake studies. To understand the mechanism by which alpha-dystrobrevin abnormalities cause muscular dystrophy, we will determine the domains of alpha-dystrobrevin that are important for rescue of the dystrophic phenotype. The proteins that associate with critical regions of alpha-dystrobrevin will then be identified. In addition, we will test the hypothesis that upregulation of alpha-dystrobrevin, which interacts with several proteins of the dystrophin complex, will ameliorate muscle degeneration in the mdx mouse. A newly-designed palmitoylated form of alpha-dystrobrevin that associates with the sarcolemma in the absence of dystrophin will be especially important in these experiments. Finally, we will examine the impact of the absence of alpha-dystrobrevin on muscle gene expression. We have conducted a thorough study of the gene changes in skeletal muscle tissue from alpha-dystrobrevin null mice using gene chip array technology. To determine which of these changes occur in muscle cells per se, as opposed to invading cells involved in the inflammatory response, we will use clonal muscle cells lines derived from satellite cells. The expression of genes that change in skeletal muscle tissue will be examined in these pure muscle cells. One particularly intriguing change, a decrease in expression of the Niemann-Pick C1 gene, will be examined in detail to determine its possible role in muscle degeneration. We expect that these studies will provide new information about the signaling capabilities of the dystrophin complex, define the role of alpha-dystrobrevin in this process, and suggest new approaches to therapy via manipulation of signal transduction mediated by the dystrophin complex.