Drosophila as a model for Emery-Dreifuss muscular dystrophy

果蝇作为埃默里-德莱福斯肌营养不良症的模型

基本信息

批准号：
8103815
负责人：
Lori L Wallrath
金额：
$ 13.17万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8103815
关键词：
Adult Affect Amino Acid Substitution Amino Acids Architecture Biological Assay C-terminal Cell Culture Techniques Cell Nucleus Cells Chromatin Clinical Trials Collaborations Collection DNA biosynthesis Defect Diagnosis Dilated Cardiomyopathy Disease Drosophila genus Emery-Dreifuss Muscular Dystrophy Exhibits Gene Expression Gene Expression Regulation Genes Genetic Genome Goals Heart failure Human In Vitro Individual Invertebrates Iowa Lamin Type A Lamins Lead Leg Lesion Link Membrane Methods Modeling Molecular Molecular Analysis Muscle Muscle Cells Muscle function Muscular Dystrophies Mutation N-terminal Neurons Nuclear Nuclear Envelope Nuclear Lamina Patients Phenotype Physiological Physiology Preclinical Drug Evaluation Process Proteins Research Research Personnel Scapuloilioperoneal Atrophy with Cardiopathy Sequence Analysis Signal Transduction Signal Transduction Pathway Skeletal Muscle Study models System Testing Therapeutic Tissue-Specific Gene Expression Tissues Transgenic Organisms Universities Variant Whole Organism citrate carrier design disease-causing mutation fly high throughput screening human disease in vivo in vivo Model medical schools mutant novel novel marker novel therapeutic intervention public health relevance reconstitution repaired retinal rods therapy development tool wasting

项目摘要

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.

描述（由申请人提供）：核纤层蛋白形成排列在内核被膜上的网状结构，为细胞核提供结构支持，并通过与染色质的接触来组织基因组。核纤层蛋白参与多种核过程，例如基因表达的调节、DNA 复制/修复和信号转导。在人类中，编码 A 型核纤层蛋白的 LMNA 基因突变会导致一系列称为核纤层蛋白病的疾病，包括常染色体显性埃默里-德莱福斯肌营养不良症 (AD-EDMD) 和扩张型心肌病。尽管核纤层蛋白几乎在所有细胞中表达，但特定组织中会出现缺陷。例如，肌肉组织对 A 型核纤层蛋白的突变形式特别敏感。我们开发了一个强大的果蝇模型来研究 A 型核纤层蛋白的功能。果蝇 A 型核纤层蛋白的突变形式与引起人类疾病的突变形式类似，已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，就会出现肌肉缺陷，导致半致死性。成虫“逃亡者”具有与幼虫肌肉功能丧失一致的腿部缺陷。在具体目标 1 中，我们将进行整个生物体药物筛选，以确定能够挽救与肌肉中表达突变形式的核纤层蛋白相关的突变表型和/或致死率的化合物。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。在具体目标 2 中，我们将测试 A 型核纤层蛋白变体的功能，这些变体已由 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体并检测分子缺陷和肌肉功能丧失来对这些变体进行功能测试。总的来说，我们的研究将临床研究与基础核纤层蛋白研究联系起来，并有可能确定用于治疗 AD-EDMD 的新化合物。公共卫生相关性：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 人患有该病。 EDMD 是被归类为“核纤层蛋白病”的十二种疾病之一，这种疾病是由编码核纤层蛋白（核膜的一个组成部分）的基因突变引起的。我们组建了一支由基础研究人员和临床医生组成的团队，他们的共同目标是确定 EDMD 的治疗方法。为了实现这一目标，我们将使用 EDMD 果蝇模型。这种无脊椎动物模型可以进行整个生物体的药物筛选。我们的研究将为核纤层蛋白提供功能测试，并鉴定可用于 EDMD 治疗的化合物。