Drosophila as a model for Emery-Dreifuss muscular dystrophy

描述（由申请人提供）：层粘连蛋白形成排列在内核包膜的网状结构，为细胞核提供结构支持，并通过与染色质的接触组织基因组。层粘连蛋白参与多种核过程，如基因表达、DNA复制/修复和信号转导的调节。在人类中，编码a型纤层蛋白的LMNA基因突变会导致一系列称为纤层病的疾病，包括常染色体显性埃默里-德莱弗斯肌营养不良症（AD-EDMD）和扩张型心肌病。虽然几乎所有细胞都表达层粘连蛋白，但缺陷只发生在特定组织中。例如，肌肉组织对a型纤层蛋白的突变形式特别敏感。我们建立了一个强大的果蝇模型来研究a型纤层蛋白的功能。果蝇a型纤层蛋白的突变形式类似于导致人类疾病的那些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，会产生肌肉缺陷，导致半致死。成年“逃亡者”具有与幼虫肌肉功能丧失一致的腿部缺陷。在Specific Aim 1中，我们将进行整个生物体的药物筛选，以确定能够挽救突变表型和/或与肌肉中表达突变形式的纤层蛋白相关的致死率的化合物。该筛选将与果蝇药物筛选专家Ross Cagan（西奈山医学院）合作进行。在特异性目标2中，我们将测试a型纤层蛋白变异的功能，这些变异已被dr。凯瑟琳·马修斯，史蒂文·摩尔和彼得·纳吉（爱荷华大学）。我们将通过在果蝇肌肉中表达这些变异并分析其分子缺陷和肌肉功能丧失来对其进行功能测试。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。

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.