Gene expression in normal & diseased muscle development

项目描述(由申请人提供)：过去十年见证了 在确定导致遗传性肌肉的原发性缺陷方面取得了显著进展 精神错乱。这些疾病的遗传异质性是巨大的；突变 有40多种不同的基因与此有关。许多关键问题仍然存在 关于这些疾病中肌肉细胞变性的发病机制 他们的治疗策略。本计划项目将使用经典方法 基因和蛋白质分析和最先进的基因表达阵列 技术来研究这些问题。这个项目的调查人员已经 对肌营养不良症领域做出了重要贡献。建议的4个 项目有独特的特点，但概念和方法重叠。 项目1将研究营养不良蛋白相关的蛋白质复合体，强调 肌聚糖和新描述的细丝-C。项目2将调查 脱铁蛋白的生物学，它潜在的蛋白质伙伴，以及它们是如何 因脱铁蛋白基因突变而改变。项目3将研究 肌管蛋白在正常肌肉发育中的作用及其机制 突变会导致发育性肌病。项目4将研究生物 以及肌肉干细胞的治疗特性。三核将提供 行政监督和服务对顺利推进 这个节目。核心B将协调样本采集和肌肉RNA 为每个项目做准备。核心C将执行微阵列分析 基因表达并提供生物信息学和数据方面的专业知识 释义。其目的是确定基因表达的模式，这些模式是 在所有营养不良中是全局性的或与特定营养不良组不同，并且 肌病；这将提供对正常肌肉的分子基础的洞察 这些疾病状态下的发育及其功能障碍。长期目标是 将这些信息与对STEM的研究的见解结合起来使用 细胞生物学设计治疗肌肉疾病的新方法 营养不良和相关的肌病。

PROGRAM DESCRIPTION (provided by applicant): The last decade has witnessed remarkable progress in defining primary defects that cause inherited muscle disorders. The genetic heterogeneity of these diseases is enormous; mutations in more than 40 different genes are implicated. Many critical questions remain concerning the pathogenesis of muscle cell degeneration in these diseases and strategies for their treatment. This Program Project will use classical methods of gene and protein analysis and state-of-the-art gene expression array technology to study these questions. The investigators in this program have contributed importantly to the muscular dystrophy field. The proposed 4 projects have unique features but overlapping concepts and methodologies. Project 1 will study the dystrophin-associated complex of proteins, emphasizing the sarcoglycans and the newly described filamin-C. Project 2 will investigate the biology of dysferlin, its potential protein partners, and how these are altered by dysferlin gene mutations. Project 3 will examine the function of myotubularin in normal muscle development and the mechanisms by which its mutations cause developmental myopathies. Project 4 will study the biological and therapeutic properties of muscle stem cells. Three Cores will provide administrative oversight and services essential to the smooth progression of this program. Core B will coordinate sample acquisition and muscle RNA preparation for each project. Core C will perform the microarray analysis of gene expression and provide expertise in bioinformatics and data interpretation. The aim is to identify patterns of gene expression that are global in all dystrophies or distinct to specific sets of dystrophies and myopathies; this will provide insight into the molecular basis of normal muscle development and its dysfunction in these disease states. The long-term goal is to use this information in conjunction with the insights from studies of stem cell biology to devise new approaches to the treatment of the muscular dystrophies and related myopathies.