Preclinical Testing of Integrin Enhancing Molecules for the Treatment of Muscular

整合素增强分子治疗肌肉萎缩症的临床前测试

基本信息

批准号：
7970910
负责人：
DEAN J. BURKIN
金额：
$ 19.04万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-18 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7970910
关键词：
Affect Binding Biological Assay Biomedical Research Cells Cessation of life Child Clinical Trials Complex Data Deterioration Development Dilated Cardiomyopathy Disease Disease Progression Dose Duchenne muscular dystrophy Dystrophin Echocardiography European Union Exercise FDA approved Fibrosis Future Gene Expression Genes Glycoproteins Human Inflammation Injury Integrins Intervention Laminin Laminin Receptor Lead Longevity Measures Mus Muscle Muscle Cells Muscle function Muscular Dystrophies Mutation Myocardium Myopathy Neuromuscular Diseases Pathology Patients Pharmaceutical Preparations Preclinical Testing Predisposition Proteins Reverse Transcriptase Polymerase Chain Reaction Skeletal Muscle Small Animal Imaging Systems Technology Testing Therapeutic Transgenic Organisms Translating United States Wasting Syndrome base drug development drug discovery effective therapy grasp improved mdx mouse mouse model muscle regeneration muscular dystrophy mouse model novel preclinical study premature prevent promoter public health relevance skeletal

项目摘要

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.

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种致命的肌肉消耗性疾病，目前尚无治愈或有效的治疗方法。 DMD 是由编码肌营养不良蛋白的基因突变导致肌营养不良蛋白缺失引起的，肌营养不良蛋白是肌肉中层粘连蛋白结合肌营养不良蛋白糖蛋白复合物的关键成分。肌营养不良蛋白的缺失会导致肌膜完整性降低并增加肌肉损伤的易感性。 1721 整合素也是肌肉中的主要层粘连蛋白受体，其在 DMD 患者和 mdx 小鼠模型中增加。这些观察结果得出这样的假设：1721 整合素是 DMD 疾病进展的主要调节因子。为了支持这一观点，肌肉中 17 整合素的转基因过度表达可减轻营养不良小鼠的肌肉疾病，而营养不良的肌肉中 17 整合素的缺失会导致更严重的疾病。这些结果共同表明，促进肌肉中 17 整合素表达增加的药物干预可能是治疗 DMD 的有效治疗方法。最近，利用一种新型的基于肌肉细胞的测定和药物发现技术，我们鉴定出了几种可以增加培养的肌肉细胞中 17 整合素表达的化合物。在这项研究中，我们将在 DMD 小鼠模型中启动这些化合物的临床前测试。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 小鼠模型的寿命并预防肌肉疾病的进展。还将使用超声心动图对化合物进行测试，以确定它们是否可以预防与肌营养不良症相关的扩张型心肌病的发展，以及是否可以预防肌肉功能的恶化。这些目标将使我们能够检验这样的假设：增加 17 整合素基因表达的化合物可以预防 DMD 小鼠模型中肌肉疾病的进展。在 DMD 小鼠模型中鉴定出增加 17 整合素表达并预防肌肉疾病的化合物将构成未来研究的基础，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。公众健康相关性：杜氏肌营养不良症 (DMD) 是一种毁灭性的肌肉疾病，影响美国和欧盟近 50,000 名儿童。 17 整合素表达的增加已被证明对 DMD 小鼠模型非常有益。本研究旨在对增强肌肉中 17 整合素表达的新药进行临床前测试，以确定它们是否对 DMD 患者具有治疗价值。