Drosophila as a model for Emery-Dreifuss muscular dystrophy

描述(申请人提供)：板层形成一个网状结构，排列在核内的包膜上，为核提供结构支持，并通过与染色质接触来组织基因组。Lamins参与多种核过程，如基因表达调控、DNA复制/修复和信号转导等。在人类中，编码A型板层蛋白的LMNA基因突变会导致一系列被称为椎板病的疾病，包括常染色体显性遗传性Emery-Dreifuss肌营养不良症(AD-EDMD)和扩张型心肌病。尽管层蛋白在几乎所有细胞中都有表达，但缺陷发生在特定的组织中。例如，肌肉组织对A型层粘连蛋白的突变形式特别敏感。我们建立了一个功能强大的果蝇模型来研究A型蛋白的功能。果蝇A型层蛋白的突变形式类似于那些在人类中引起疾病的突变形式，已经在转基因果蝇中表达。当这些突变形式在幼虫肌肉中表达时，肌肉缺陷就会出现，导致半致死性。成年“逃跑者”的腿部缺陷与幼虫肌肉功能的丧失一致。在特定的目标1中，我们将进行整个有机体的药物筛选，以确定拯救与肌肉中表达突变形式的层蛋白相关的突变表型和/或致命性的化合物。本片将与Ross Cagan(Mt.西奈医学院)，果蝇药物筛选的专家。在具体目标2中，我们将测试由爱荷华大学的凯瑟琳·马修斯、史蒂文·摩尔和彼得·纳吉博士在患者身上发现的A-型层粘连蛋白变体的功能。我们将通过在果蝇肌肉中表达它们并分析分子缺陷和肌肉功能丧失来测试这些变体的功能。总的来说，我们的研究将临床研究与基础层粘连蛋白研究联系起来，并有可能确定治疗AD-EDMD的新化合物。 与公共卫生相关：Emery-Dreifuss肌营养不良症(EDMD)是一种罕见的肌营养不良症，会导致进行性肌肉萎缩和心力衰竭，估计有1-2/100,000人发生。EDMD是被归类为“椎板病症”的12种疾病之一，这种疾病是由编码核膜成分层粘连蛋白的基因突变引起的。我们已经组建了一个由基础研究人员和临床医生组成的团队，他们共同的目标是确定EDMD的治疗方法。为了达到这个目标，我们将使用EDMD的果蝇模型。这种无脊椎动物模型允许对整个有机体进行药物筛选。我们的研究将提供Lamins的功能测试，并确定可能治疗EDMD的化合物。

DESCRIPTION (provided by applicant): Lamins form a meshwork that lines the inner nuclear envelope, providing structural support for the nucleus and organizing the genome through contacts made with chromatin. Lamins participate in diverse nuclear processes such as the regulation of gene expression, DNA replication/repair and signal transduction. In humans, mutations in the LMNA gene, encoding the A-type lamins, cause a collection of diseases known as laminopathies, including autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) and dilated cardiomyopathy. Though lamins are expressed in nearly all cells, defects occur in specific tissues. For example, muscle tissue is especially sensitive to mutant forms of A-type lamin. We developed a powerful Drosophila model for studying the function of A-type lamins. Mutant forms of the Drosophila A-type lamin analogous to those that cause disease in humans have been expressed in transgenic flies. When these mutant forms are expressed in larval muscle, muscle defects arise that result in semi-lethality. Adult "escapers" possess leg defects consistent with a loss of larval muscle function. In Specific Aim 1 we will perform a whole organism drug screen to identify compounds that rescue the mutant phenotypes and/or lethality associated with expressing mutant forms of lamin in muscle. This screen will be carried out in collaboration with Ross Cagan (Mt. Sinai School of Medicine), an expert in Drosophila drug screens. In Specific Aim 2 we will test the function of A-type lamin variants that have been identified in patients by Drs. Katherine Matthews, Steven Moore and Peter Nagy (University of Iowa). We will functionally test these variants by expressing them in Drosophila muscle and assaying for molecular defects and loss of muscle function. Collectively, our studies link clinical investigations with basic lamin research and have the potential to identify new compounds for the treatment of AD-EDMD. PUBLIC HEALTH RELEVANCE: Emery-Dreifuss muscular dystrophy (EDMD), a rare form of muscular dystrophy that causes progressive muscle wasting and cardiac failure, is estimated to occur in 1-2/100,000 individuals. EDMD is one of twelve diseases classified as "laminopathies", which are caused by mutations in the gene encoding lamin, a component of the nuclear envelope. We have assembled a team of basic researchers and clinicians that share the goal of identifying a therapy for EDMD. To reach this goal we will use a fruit fly model of EDMD. This invertebrate model allows for whole organism drug screens. Our studies will provide functional tests for lamins and identify compounds for possible therapeutic treatment of EDMD.