Preserving mitochondrial function for alleviating ALS progression

保护线粒体功能以缓解 ALS 进展

基本信息

批准号：
10366061
负责人：
Marco Brotto
金额：
$ 57.08万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10366061
关键词：
ALS pathology ALS patients Address Affect Amyotrophic Lateral Sclerosis Autopsy Bacteria Biochemical Biology Biopsy Specimen Brain Butyrates Cell model Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Colon Communication Data Defect Denervation Dietary Fiber Dietary Supplementation Disease Progression Electrophysiology (science)Etiology Feedback Fermentation Functional disorder Genes Genetic Hand Strength Hormones Human Human Pathology Intervention Intestines Knowledge Leaky Gut Link Lipids Longevity Mediating Mediator of activation protein Metabolic Mitochondria Molecular Morphology Motor Neurons Mus Muscle Muscle Fibers Muscle Mitochondria Mutation Neuromuscular Diseases Neuromuscular Junction Neurons Organ Oxidative Stress Paralysed Pathogenesis Pathology Performance Physiological Physiology Play Predisposition Probiotics Production Property Quality of life Reactive Oxygen Species Reporting Research Role Series Signal Transduction Skeletal Muscle Spinal Cord Supplementation Symptoms Testing Therapeutic Transgenes Volatile Fatty Acids Withdrawal amyotrophic lateral sclerosis therapy dietary dysbiosis experimental study familial amyotrophic lateral sclerosis gastrointestinal gut bacteria gut homeostasis gut microbiome improved intestinal homeostasis lipidomics live cell imaging microbiome mitochondrial dysfunction mouse model muscle metabolism neuromuscular neuromuscular function neuromuscular system neuron loss novel novel therapeutic intervention preservation response restoration skeletal muscle wasting sporadic amyotrophic lateral sclerosis superoxide dismutase 1 tool translational potential

项目摘要

Project Summary Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease without cure. Most ALS are sporadic cases without identified genetic causes. However, the spinal cord and muscle autopsy/biopsy samples from both sporadic and familial ALS patients all show remarkable defects in morphology and biochemical properties of mitochondria. This indicates abnormal mitochondria as a common player in neuromuscular degeneration despite the etiology. Our research using the ALS mouse models (G93A), over the last 12 years, establishes a concept that mitochondrial dysfunction in skeletal muscle is part of the pathogenesis of ALS. Muscle appears to be a primary target of ALS mutation, in addition to being victim of neuronal withdrawal, because mitochondrial defects in muscle feedback to neuromuscular junction (NMJ) remodeling in ALS. Thus, restoration of mitochondrial function is a logical approach to alleviate the systemic symptom of ALS through fixing a common pathology. We made a novel discocery that ALS progression includes a leaky gut with an imbalanced microbiome (dysbiosis) in G93A mice. This gut defects occurs before the onset of ALS neuromuscular symptoms, suggesting that gut defects may play a role in ALS progression. We reported that the colon of G93A mice contained less butyrate-producing bacteria, and the dietary butyrate supplementation alleviated gut defects in G93A mice, improving their neuromuscular performance and extending their life span. Thus, our study brought a new concept that restoring gut homeostasis may provide an alternative means for improving neuromuscular function to treat ALS. Since the original submission, our collaboration with the Brotto Lab made several exciting new discoveries. We identified altered Lipidomics Profiles of ROS-related Bioactive Lipids (BLs) in muscle that were restored by one-month butyrate diet supplementation in G93A mice. Further, butyrate treatment directly enhanced muscle contractility. Our preliminary data also show that butyrate treatment improved mitochondrial function and its susceptibility to oxidative-stress induced damage in G93A muscle fibers. Our data suggest that butyrate could be an important mediator regulating the neuromuscular-gut integrative physiology. We hypothesize that integrative signaling between the neuromuscular system and gut contributes to the progressive loss of mitochondrial function in ALS, and restoration of butyrate- related microbiome has benefits in preserving mitochondrial function for treatment of ALS. The proposed study will address two fundamental questions: How do gut defects contribute to mitochondrial dysfunction of neuromuscular system in ALS (Aim 1)? Can neuromuscular-gut signaling be leveraged to improve mitochondrial function to slow ALS progression and/or improve the life quality of ALS patients (Aim 2)? While altered intestinal homeostasis and microbiome is linked to the human pathology of ALS, we anticipate that our study will bring novel concepts to the ALS research field. Knowledge gained from this study can have potential translational implications for developing new therapeutic strategies for combating ALS.

项目摘要肌萎缩性外侧硬化症（ALS）是一种致命的神经肌肉疾病，无法治愈。大多数ALS是零星的没有鉴定出遗传原因的病例。但是，脊髓和肌肉尸检/活检样本零星和家族性ALS患者均表现出显着的形态和生化特性缺陷线粒体。这表明线粒体异常是神经肌肉变性的常见参与者尽管存在病因。在过去的12年中，我们使用ALS Mouse模型（G93A）的研究建立了一个骨骼肌中线粒体功能障碍是ALS发病机理的一部分。肌肉出现除了成为神经元戒断的受害者外，要成为ALS突变的主要目标，因为 ALS中神经肌肉连接（NMJ）重塑的肌肉反馈中的线粒体缺陷。因此，线粒体功能的恢复是减轻ALS系统症状的逻辑方法修复常见的病理。我们做了一个新颖的乳液，ALS的进展包括一个漏水的肠道 G93A小鼠中的微生物组不平衡的微生物组。这种肠道缺陷发生在ALS发作之前神经肌肉症状，表明肠道缺陷可能在ALS进展中起作用。我们报告了这一点 G93A小鼠的结肠含有较少的丁酸酯细菌和饮食中的丁酸酯补充剂缓解了G93A小鼠的肠道缺陷，改善了神经肌肉的表现并延长了其寿命。因此，我们的研究带来了一个新概念，即恢复肠道稳态可能会为改善神经肌肉功能以治疗ALS。自最初提交以来，我们与Brotto的合作实验室做出了一些令人兴奋的新发现。我们确定了与ROS相关的生物活性的改变的脂质组学轮廓肌肉中的脂质（BLS）是通过G93A小鼠中补充一个月丁酸酯饮食恢复的。更远，丁酸治疗直接增强了肌肉收缩力。我们的初步数据还表明丁酸酯治疗改善了线粒体功能及其对G93A中氧化压力诱导损伤的敏感性肌肉纤维。我们的数据表明，丁酸酯可能是调节神经肌肉gut的重要介体综合生理学。我们假设神经肌肉系统和肠道有助于ALS中线粒体功能的进行性丧失，并恢复丁酸酯 - 相关的微生物组在维护线粒体功能方面具有优势用于治疗ALS。这拟议的研究将解决两个基本问题：肠道缺陷如何有助于线粒体 ALS中神经肌肉系统功能障碍（AIM 1）？可以将神经肌肉旋转信号传导提高线粒体功能以减慢ALS的进展和/或提高ALS患者的生活质量（AIM 2）？虽然改变的肠内稳态和微生物组与ALS的人类病理有关，但我们预计我们的研究将为ALS研究领域带来新颖的概念。从这项研究中获得的知识可以为制定对抗ALS的新治疗策略具有潜在的翻译意义。