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

描述(由申请人提供)：这项建议的目的是开发新的小分子药物来治疗杜兴，可能还有其他肌营养不良症。我们选择了四个靶点，如果蛋白质水平增加或减少，就可以改变疾病的过程。我们的四个靶点是：utroin(UTRN)、myostatin(GDF8)、IGF-1a类剪接形式(IGF-1a)和&lt；x7-整合素(ITGA7)。其他人(在某些情况下还包括我们自己)的研究表明，适度增加utroin、IGF-1a或ITGA7的水平可以显著改善与dystrophin和/或UTRN基因突变相关的小鼠肌肉无力。同样，抑制GDF8已被证明可以改善携带dystrophin基因(MDX)突变的小鼠的肌肉生长和再生。 我们已经构建了这份U54提案，其中包含一个总体项目和四个核心，以执行(1)药物化学；(2)药理学；(3)毒理学；以及(4)潜在药物的疗效评估，以调整我们的四个目标。我们在高通量筛选(HTS)平台中使用了小分子基因表达调制(GEMS)技术，以识别调节我们的靶标表达的小分子，这些小分子已经在肌肉营养不良的动物模型中得到验证。我们已经通过HTS发现了多种化合物，它们在培养的肌肉细胞中调节我们的四个靶点。我们现在需要开始迭代过程，将这些最初的成功转化为药物。因此，这项研究提案的最终目标是识别、表征和优化可用于临床环境中治疗肌营养不良症的小分子。

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.