Clinical & Molecular Analysis of Neuromuscular Disorders

描述(申请人提供)：自20世纪80年代中期以来，科学已经取得了 在理解遗传学方面取得了巨大的进步，包括基因 在某些疾病中发挥作用。特别是，已经取得了重大进展。 有助于确定神经肌肉疾病的分子基础。这些 最近的发现启动了基于基因的疗法的令人兴奋的研究。 我们实验室的重点一直放在临床和分子发病机制上。 伊利诺伊州中部家庭独特的神经肌肉疾病。这个 最初的K02拨款是用于临床和分子描述一种独特的 在一个患有CharcotMarieTooth和耳聋的大家庭中结合了各种功能。 这项正在进行的研究已经发现了一种独特的突变 与疾病表型共分离的PMP22基因。我们已经招募了 更多的家庭，以提高我们对这种有趣的表型的理解。 分子研究建议通过以下方法来研究听力损失的机制 PMP22在小鼠耳蜗组织中的表达 开发和鉴定与耳聋相关的新的PMP22突变。 由于我们对神经肌肉疾病的兴趣，我们已经扩大了我们的 研究兴趣包括另一种独特的疾病：常染色体显性遗传 肢带型肌营养不良合并Paget病 一些人患有阿尔茨海默病。我们已经将这种疾病映射到了一种独特的 关注9号染色体。我们研究的重点是识别 会破坏基本的细胞功能，并导致这个家族中的无数表型。 目前拨款的目的是发展分子和分析技术。 这将促进我们对CharcotMarieTooth病的理解，跛带病 肌营养不良症和其他神经肌肉疾病。建议的培训 将为PI提供必要的技能，以调查临床和基础 这些疾病的分子发病机制及其对新药开发的帮助 治疗方案。

DESCRIPTION (provided by applicant): Since the mid1980s, science has made tremendous progress in understanding genetics, including the roles that genes play in certain diseases. In particular, significant strides have been made towards identifying the molecular basis of neuromuscular disorders. These recent findings have initiated exciting studies of genebased therapies. The focus of our laboratory has been on the clinical and molecular pathogenesis of unique neuromuscular diseases of families from Central Illinois. The original K02 grant was for clinical and molecular delineation of a unique combination of features in a large family with CharcotMarieTooth and deafness. This ongoing study has led to the identification of a unique mutation in the PMP22 gene that cosegregates with the disease phenotype. We have recruited additional families to improve our understanding of this interesting phenotype. Molecular studies propose to examine the mechanism of hearing loss by determining patterns of PMP22 expression in the cochlea of mice throughout development and identifying new PMP22 mutations associated with deafness. As a result of our interest in neuromuscular disorders we have expanded our research interests to include another unique disorder: autosomal dominant limbgirdle muscular dystrophy in combination with Paget disease of bone and Alzheimer disease in some individuals. We have mapped this disorder to a unique focus on chromosome 9. The focus of our research is to identify the gene that disrupts basic cell function and causes a myriad of phenotypes in this family. The aim of the current grant is to develop molecular and analytical techniques that will advance our understanding of CharcotMarieTooth disease, limbgirdle muscular dystrophy and other neuromuscular disorders. The suggested training will provide the PI with skills necessary to investigate the clinical and basic molecular pathogenesis of these disorders and aid in the development of novel treatment protocols.