Skeletal Muscle Mechanisms of Disease in ALS

ALS 的骨骼肌疾病机制

基本信息

批准号：
8212194
负责人：
LEE J MARTIN
金额：
$ 35.16万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2010-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212194
关键词：
Adenine Nucleotides Adult Amyotrophic Lateral Sclerosis Animal Model Apoptosis Atrophic Attenuated Automobile Driving Biology Cell Culture Techniques Cell model Cells Cessation of life Coculture Techniques Cultured Cells Development Disease Disease Progression Disorder by Site Distal Environmental Risk Factor Familial Amyotrophic Lateral Sclerosis Fluorescence Resonance Energy Transfer Fluorescent Probes Gene Deletion Genes Genetic Risk Genetic Variation Grant Health Human In Vitro Inherited Ion Channel Lead Life Limb structure Measures Mediating Mediator of activation protein Microscopy Mitochondria Modeling Molecular Target Motor Neuron Disease Motor Neurons Mus Muscle Muscle Fibers Muscle Mitochondria Muscle denervation procedure Mutation Myoblasts Myopathy Neurodegenerative Disorders Neurologic Neuromuscular Diseases Neuromuscular Junction Nitrogen Oxidation-Reduction Oxidative Stress Oxygen Paralysed Paresis Pathogenesis Pathologic Pathologic Processes Pathology Permeability Phenotype Production Proteins Research Personnel Role SOD1 gene Site Skeletal Muscle Spinal Cord System Testing Tissues Toxic effect Transgenic Mice Variant Voltage-Dependent Anion Channel Whole-Cell Recordings Work age related axonopathy base cellular imaging cyclophilin D deprivation drug discovery effective therapy in vivo mitochondrial permeability transition pore motor deficit motor neuron degeneration mutant nitration novel oxidation oxidative damage promoter superoxide dismutase 1 therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is the 3rd most common human neurodegenerative disease with an adult onset. It is a fatal paralytic disease of motor neurons (MNs) without any effective treatments. Novel mechanism-based targets need to be identified for drug discovery relevant to diseased MNs. Some forms of ALS are inherited and are caused by mutations in the superoxide dismutase-1 (SOD1) gene, thus providing a clue about MN vulnerability. Many different SOD1 mutations occur, but the mechanisms of human SOD1 (hSOD1) toxicity to MNs are unresolved. Importantly, the autonomy of the MN degeneration in ALS is an important unresolved problem. We hypothesize that skeletal muscle is a primary site of pathogenesis in ALS that triggers MN degeneration. We have created new transgenic (tg) mice with skeletal muscle-specific expression of hSOD1 gene variants. These hSOD1mus tg mice develop neurologic and pathologic phenotypes consistent with ALS. Using these novel mice we propose to study skeletal muscle as a disease-causing entity in ALS. In Aim 1 we will analyze the age-related neurologic and pathologic phenotypes of hSOD1mus tg mice. We hypothesize that the mechanisms of MN degeneration in our hSOD1mus tg mice are consistent with distal axonopathy and target deprivation-induced apoptosis. In Aim 2, we will analyze the involvement of oxidative stress and activation of the mitochondrial permeability pore in skeletal muscle as mediators of muscle pathology in hSOD1mus tg mice. In Aim 3 we will use cultured cells to examine if hSOD1 expression in skeletal muscle cells alters their intracellular redox state, Ca2+ handling, and ion channel function and disrupts the neuromuscular junction, thus provoking MN degeneration. The work can lead to new concepts about the non-autonomous death of MNs in ALS pathogenesis. The discovery of instigating toxicities or disease progression determinants within skeletal muscle would be very valuable for development of new effective therapies in the treatment and cure of ALS. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder. This work will determine if abnormalities in skeletal muscle have causal roles in the disease mechanisms. Skeletal muscle could provide new tissue- and molecular targets for drug discovery in ALS.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是成人发作的第三种最常见的人类神经退行性疾病。它是运动神经元（MN）的致命麻痹性疾病，没有任何有效的治疗方法。需要确定基于机制的新型靶标，以发现与患病MN有关的药物发现。某些形式的ALS是遗传的，是由超氧化物歧化酶1（SOD1）基因突变引起的，因此提供了有关MN脆弱性的线索。发生了许多不同的SOD1突变，但是人类SOD1（HSOD1）对MN的毒性的机制尚未解决。重要的是，ALS中MN变性的自治是一个重要的未解决的问题。我们假设骨骼肌是触发MN变性的ALS发病机理的主要部位。我们已经创建了新的转基因（TG）小鼠，它具有HSOD1基因变体的骨骼肌特异性表达。这些HSOD1MUS TG小鼠会发展与ALS一致的神经系统和病理表型。使用这些新颖的小鼠，我们建议将骨骼肌研究为ALS中引起疾病的实体。在AIM 1中，我们将分析HSOD1MUS TG小鼠的年龄相关神经和病理表型。我们假设我们的HSOD1MUS TG小鼠中Mn变性的机制与远端轴突病和靶剥夺诱导的凋亡一致。在AIM 2中，我们将分析氧化应激的参与以及线粒体通透性孔在骨骼肌中的激活，作为HSOD1MUS TG小鼠肌肉病理学的介体。在AIM 3中，我们将使用培养的细胞检查骨骼肌细胞中的HSOD1表达是否改变了其细胞内氧化还原态，Ca2+处理和离子通道功能，并破坏神经肌肉连接，从而引起MN变性。这项工作可能导致有关MN在ALS发病机理中非自治死亡的新概念。在骨骼肌内发现促进毒性或疾病进展决定因素的发现对于开发ALS治疗和治愈的新有效疗法非常有价值。公共卫生相关性：肌萎缩性侧索硬化症（ALS）是一种致命的神经肌肉疾病。这项工作将确定骨骼肌的异常是否在疾病机制中具有因果作用。骨骼肌可以为ALS中的药物发现提供新的组织和分子靶标。