Anatomic variations in muscle gene expression

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，他希望获得成为一名独立内科科学家所需的培训。他计划研究肌肉营养不良的病理生理学，并学习基因组学和生物化学课程。环境由导师、同事和合作者组成，他们拥有此类培训所需的专业知识，以及设备齐全的实验室。这位候选人希望利用基因组技术将动物模型与人类疾病联系起来，并确定神经肌肉疾病的药物治疗目标。该研究项目解决了不同骨骼肌在肌营养不良症中的选择性参与。这一发现长期以来一直没有得到解释，不能完全归因于解剖学或组织学特征。基因表达技术和不同的表现型为探讨这个问题提供了一种新的方法。总体假设是，肌肉之间在分子水平上的差异与它们对遗传侮辱的不同反应有关；这些差异将在正常肌肉和发育不良的肌肉中进行检验。目标1是利用基因表达分析创建人类骨骼肌群的分子图谱。所得到的数据将与小鼠肌肉的现有数据进行比较；物种间的关联将有助于解释小鼠的治疗试验。目的2研究肢体带状肌营养不良2B和Miyoshi肌病两种不同表型的肌肉标本之间的基因表达差异。目标3是对目标1和目标2中确定的基因的蛋白质产物进行分析，以确定与deferlin和dystrophin的关联。被确定为与dyferlin和dystrophin相互作用的蛋白质可能是药物治疗的潜在靶点。

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.