Preclinical Testing of Integrin Enhancing Molecules for the Treatment of Muscular

描述(申请人提供)：杜氏肌营养不良症(DMD)是一种致命的肌肉萎缩疾病，目前还没有治愈或有效的治疗方法。DMD是由于编码dystrophin的基因突变导致dystrophin蛋白的缺失引起的，dystrophin蛋白是肌肉中层粘连蛋白结合dystrophin糖蛋白复合体的关键成分。肌营养不良蛋白的缺失会导致肌膜完整性降低，增加肌肉损伤的易感性。1721整合素也是肌肉中的一种主要的层粘连蛋白受体，在DMD患者和MDX小鼠模型中增加。这些观察结果导致假设1721整合素是DMD疾病进展的主要修饰物。支持这一观点的是，在肌肉中过表达17整合素转基因可以缓解营养不良小鼠的肌肉疾病，而营养不良肌肉中17整合素的缺失会导致更严重的疾病。综上所述，这些结果表明，促进肌肉中17整合素表达增加的药物干预可能是治疗DMD的有效方法。最近，利用一种新的基于肌肉细胞的检测和药物发现技术，我们已经鉴定出几种化合物，它们可以增加培养的肌肉细胞中17整合素的表达。在这项研究中，我们将启动这些化合物在DMD小鼠模型中的临床前测试。我们的研究将确定这些化合物的最佳剂量，并确定它们是否可以延长DMD小鼠模型的寿命并防止肌肉疾病的进展。还将测试化合物，以确定它们是否通过超声心动图防止与肌营养不良相关的扩张型心肌病的发展，以及它们是否防止肌肉功能的恶化。总之，这些目标将使我们能够检验这样一个假设，即增加17个整合素基因表达的化合物可以防止DMD小鼠模型的肌肉疾病进展。在DMD小鼠模型中识别增加17整合素表达和预防肌肉疾病的化合物将为未来的研究奠定基础，这些研究将把我们的基础生物医学研究转化为DMD临床试验药物的开发。 与公共卫生相关：Duchenne肌营养不良症(DMD)是一种毁灭性的肌肉疾病，在美国和欧盟影响着近5万名儿童。在DMD小鼠模型中，增加17整合素的表达被证明是非常有益的。本研究旨在对增强肌肉整合素表达的新型药物进行临床前测试，以确定它们是否对DMD患者具有治疗价值。

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is a lethal muscle wasting disease for which there is currently no cure or effective treatment. DMD is caused by mutations in the gene encoding dystrophin resulting in an absence of the dystrophin protein, a critical component of the laminin binding dystrophin glycoprotein complex in muscle. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The 1721 integrin is also a major laminin receptor in muscle that is increased in DMD patients and the mdx mouse model. These observations led to the hypothesis that the 1721 integrin is a major modifier of disease progression in DMD. In support of this idea, transgenic over-expression of the 17 integrin in muscle alleviates muscle disease in dystrophic mice, while loss of 17 integrin in dystrophic muscle results in more severe disease. Together these results indicate pharmacological interventions which promote increased 17 integrin expression in muscle may be an effective therapeutic approach for the treatment of DMD. Recently, using a novel muscle cell-based assay and drug discovery technology, we have identified several compounds that increase 17 integrin expression in cultured muscle cells. In this study we will initiate preclinical testing of these compounds in mouse models of DMD. Our studies will determine the optimal dose of these compounds and determine if they increase longevity and prevent muscle disease progression in DMD mouse models. Compounds will also be tested to determine if they prevent the development of dilated cardiomyopathy associated with muscular dystrophy using echocardiography and if they prevent deterioration in muscle function. Together these aims will allow us to test the hypothesis that compounds which increase 17 integrin gene expression can prevent muscle disease progression in mouse models of DMD. The identification of compounds that increase 17 integrin expression and prevent muscle disease in mouse models of DMD will form the basis of future studies that will translate our basic biomedical research into the development of drugs for clinical trials for DMD. PUBLIC HEALTH RELEVANCE: Duchenne Muscular Dystrophy (DMD) is a devastating muscle disease that affects nearly 50,000 children in the United States and European Union. Increased expression of 17 integrin has been shown to be enormously beneficial in DMD mouse models. This study aims to conduct preclinical testing of novel drugs that enhanced 17 integrin expression in muscle to determine if they maybe of therapeutic value to DMD patients.