Anatomic variations in muscle gene expression

肌肉基因表达的解剖学变异

• 批准号: 7050111
• 负责人: PETER B. KANG
• 金额: $ 16.81万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-06 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050111
• 关键词: children; clinical research; dystrophin; gene expression profiling; gene mutation; human tissue; laboratory mouse; muscle proteins; muscular dystrophy; myotubes; protein localization; protein protein interaction; tissue /cell culture

DESCRIPTION (provided by applicant): The candidate is a pediatric neurologist specializing in neuromuscular diseases who wishes to acquire the training needed to become an independent physician scientist. He plans to study the pathophysiology of the muscular dystrophies and take courses in genomics and biochemistry. The environment consists of mentors, colleagues, and collaborators who have the expertise needed for such training, as well as a well equipped laboratory. The candidate hopes to use genomic techniques to correlate animal models to human disease and identify targets for the pharmacologic treatment of neuromuscular diseases. The research project addresses the selective involvement of different skeletal muscles in the muscular dystrophies. This finding has long remained unexplained, and cannot be attributed solely to anatomic or histologic features. Gene expression techniques and divergent phenotypes among the dysferlinopathies provide a new means of approaching this question. The overall hypothesis is that differences between muscles at the molecular level are related to their varying responses to genetic insults; these differences will be examined in both normal and dysferlin-deficient muscle. Aim 1 is to create a molecular map of human skeletal muscle groups using gene expression analysis. The resulting data will be compared to that already available for mouse muscles; the interspecies correlation will assist in the interpretation of therapeutic trials in mice. Aim 2 is to identify gene expression differences between muscle specimens obtained from individuals displaying two different phenotypes of dysferlin deficiency, limb girdle muscular dystrophy 2B and Miyoshi myopathy. Aim 3 is to perform analyses on the protein products of genes identified in Aims 1 and 2 to determine associations with dysferlin and dystrophin. Proteins that are determined to interact with dysferlin and dystrophin may be potentially targets for pharmacologic therapies.

描述（由申请人提供）： 候选人是一名专门研究神经肌肉疾病的儿科神经科医生，他们希望获得成为独立医师科学家所需的培训。他计划研究肌肉营养不良的病理生理学，并接受基因组学和生物化学课程。环境由具有此类培训所需的专业知识以及设备齐全的实验室所需的专业知识的导师，同事和合作者组成。候选人希望使用基因组技术将动物模型与人类疾病相关联，并确定对神经肌肉疾病的药理治疗的靶标。该研究项目涉及不同骨骼肌在肌肉营养不良中的选择性参与。这一发现长期以来一直无法解释，不能仅归因于解剖学或组织学特征。屈服症状病变中的基因表达技术和发散的表型提供了一种解决这个问题的新方法。总体假设是，分子水平的肌肉之间的差异与它们对遗传侮辱的不同反应有关。这些差异将在正常和dysferlin缺乏的肌肉中进行检查。目的1是使用基因表达分析创建人类骨骼肌群的分子图。将最终的数据与已经可用于小鼠肌肉的数据进行比较；种间相关性将有助于解释小鼠的治疗试验。目的2是确定从表现出两种不同表型缺乏表型的个体获得的肌肉样本之间的基因表达差异，肢体束肌营养不良2B和宫菌肌病。 AIM 3是对目标1和2中鉴定的基因蛋白质产物进行分析，以确定与Dysferlin和Dysrotrophin的关联。确定与Dysferlin相互作用和肌营养不良蛋白相互作用的蛋白质可能是药物治疗的潜在靶标。