Development of novel small molecules for delaying the progression of muscular dy

描述（由申请人提供）：本提案的目的是开发新的小分子药物，用于治疗杜氏肌营养不良症，以及可能的其他肌营养不良症。我们选择了四个靶点，如果蛋白质水平升高或降低，它们可以改变疾病的进程。我们的四个靶标是：UTRN （UTRN）、GDF8（肌生长抑制素）、la类剪接形式的胰岛素样生长因子（IGF-la）和<x7-整合素（ITGA7）。其他人（在某些情况下是我们自己）的研究表明，适度增加肌营养蛋白、IGF-la或ITGA7的水平，可以显著改善老鼠体内与肌营养不良蛋白和/或UTRN基因突变相关的肌肉无力。同样，抑制GDF8已被证明可以改善肌营养不良蛋白基因（mdx）突变小鼠的肌肉生长和再生。

Description (provided by applicant): The purpose of this proposal is to develop new small molecule drugs for the treatment of Duchenne, and possibly other muscular dystrophies. We have chosen four targets that can alter the disease process if the protein levels are either increased or decreased. Our four targets are: utrophin (UTRN), myostatin (GDF8), the class la splice-form of insulin-like growth factor (IGF-la), and <x7-integrin (ITGA7). Work by others (and in some cases ourselves) has demonstrated that a modest increase in the levels of utrophin, IGF-la or ITGA7 can significantly improve the muscle weakness associated with mutations in the dystrophin and/or UTRN genes in mice. Similarly, inhibition of GDF8 has been shown to improve muscle growth and regeneration in mice harboring a mutation in the dystrophin gene (mdx) mice. We have constructed this U54 proposal with one overarching project and four cores to perform (1) medicinal chemistry; (2) pharmacology; (3) toxicology; and (4) efficacy assessment of potential drugs to modulate our four targets. We have used the Gene Expression Modulation by Small molecules (GEMS) technology in a high-throughput screening (HTS) platform to identify small molecules that modulate expression of our targets that have been validated in animal models of muscular dystrophy. We have discovered multiple compounds via the HTS that modulate our four targets in muscle cells in culture. We now need to begin the iterative process that will turn these initial hits into drugs. Thus, the ultimate goal of this research proposal is to identify, characterize and optimize small molecules that can be used in a clinical setting to treat muscular dystrophy.