Pathogenesis of Emery-Dreifuss Muscular Dystrophy

描述(申请人提供)：Emery-Dreifuss肌营养不良症(EDMD)的特征是某些肌肉群无力和消瘦，早期收缩和危及生命的心肌病。EDMD可由编码核膜蛋白的两个基因突变引起。常染色体显性EDMD和罕见常染色体隐性遗传病是由LMNA突变引起的。LMNA编码A型核层蛋白，即与核内膜相关的中间丝蛋白。X连锁EDMD是由EMD突变引起的，EMD编码内核膜的一种完整蛋白质，称为Emerin，与A型板层相互作用。虽然EDMD受试者的遗传突变和表型异常已经被很好地描述，但对其发病机制或两种不同核膜蛋白的变化如何导致相同的疾病却知之甚少。在这个项目的当前阶段，我们取得了新的发现，提供了一个连贯的和可测试的致病模型来解释EDMD肌肉损伤的发展。在常染色体和X连锁EDMD的小鼠模型中，我们已经显示在肌肉损伤发生之前，MAP激酶级联的ERK和JNK分支被激活。我们进一步表明，药物抑制ERK信号可以预防其中一种小鼠模型的心肌病。基于这些结果，我们假设EMD和LMNA的突变导致核膜异常，从而导致MAP激酶的激活。在心肌细胞中，这些MAP激酶激活一组导致心肌病的“下游”基因。在这个项目中，我们将检验这一假设。在目标1中，我们将研究A型Lamins和Emerin之间的联系，研究在EDMD患者中发现的缺乏A型lamins或表达带有氨基酸替换的lamins的细胞中Emerin的翻转。我们还将在常染色体EDMD小鼠模型中检测Emerin在受累肌肉中的亚细胞定位。AIM 2被设计用来检测A型层粘连蛋白和新生蛋白改变细胞中的MAP激酶信号通路。这一目标的主要目的是确定核膜蛋白的改变如何激活MAP激酶，并测试Emerin或A-型层蛋白的逆转改变是否改善了信号异常。在目标3中，我们将开展遗传学和临床前药理学研究，以确定阻断MAP激酶信号是否可以预防EDMD小鼠模型的心肌病。该项目取得的成果将确定EDMD和由LMNA和EMD突变引起的相关疾病的治疗干预目标。公共卫生相关性：肌肉营养不良总体上对健康有很大影响，仅在美国就有数万人受到影响。Emery-Dreifuss肌肉病的特征是某些肌肉萎缩、关节畸形和危及生命的心脏问题，这些问题可能导致过早和猝死。目前还没有针对Emery-Dreifuss肌营养不良症或相关疾病的确切治疗方法；因此，该项目的工作旨在确定细胞和动物模型中的靶点，从而为患者提供治疗。

DESCRIPTION (provided by applicant): Emery-Dreifuss muscular dystrophy (EDMD) is characterized by weakness and wasting of certain muscle groups, early contractures and a life-threatening cardiomyopathy. EDMD can result from mutations in two genes encoding proteins of the nuclear envelope. Autosomal dominant EDMD and infrequent autosomal recessive cases result from mutations in LMNA. LMNA encodes A-type nuclear lamins, intermediate filament proteins associated with the inner nuclear membrane. X-linked EDMD is caused by mutations in EMD, which encodes an integral protein of the inner nuclear membrane called emerin that interacts with A-type lamins. While the genetic mutations and phenotypic abnormalities in subjects with EDMD have been well described, much less is known about pathogenesis or how alterations in two different nuclear envelope proteins cause the same disease. During the current period of this project, we made new discoveries that provide a coherent and testable pathogenic model to explain the development of muscle damage in EDMD. We have shown activation of the ERK and JNK branches of the MAP kinase cascade, prior to the development of muscle damage, in hearts of mouse models of autosomal and X-linked EDMD. We have further shown that pharmacological inhibition of ERK signaling prevents cardiomyopathy in one of these mouse models. Based on these results, we hypothesize that mutations in EMD and LMNA cause nuclear envelope abnormalities that lead to activation of MAP kinases. In cardiomyocytes, these MAP kinases activate a set of "downstream" genes that leads to cardiomyopathy. In this project, we will test this hypothesis. In Aim 1, we will investigate the link between A- type lamins and emerin, examining the turn over of emerin in cells lacking A-type lamins or expressing lamins with amino acid substitutions found in subjects with EDMD. We will also examine emerin subcellular localization in affected muscle in a mouse model of autosomal EDMD. Aim 2 is designed to examine MAP kinase signaling pathways in cells with A-type lamin and emerin alterations. The main goals of this aim are to determine how alterations in nuclear envelope proteins activate MAP kinases and to test if reversing alterations in emerin or A-type lamins ameliorates signaling abnormalities. In Aim 3, we will carry out genetic and preclinical pharmacological studies to determine if blocking MAP kinase signaling prevents cardiomyopathy in a mouse model of EDMD. The results obtained in this project will identify targets for therapeutic interventions in EDMD and related disorders caused by LMNA and EMD mutations. PUBLIC HEALTH RELEVANCE: Muscular dystrophies collectively have a high impact on health, affecting tens of thousands of people in the United States alone. Emery-Dreifuss muscular is characterized by wasting of certain muscles, joint deformities and life-threatening heart problems that can result in premature and sudden death. There is currently no definitive therapy for Emery-Dreifuss muscular dystrophy or related diseases; therefore, the work in this project is designed to identify targets in cellular and animal models that can lead to treatments for patients.