ATG13: A new player in ME/CFS

ATG13：ME/CFS 的新玩家

• 批准号: 10666899
• 负责人: AVIK ROY
• 金额: $ 22.5万
• 依托单位: SIMMARON RESEARCH INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666899
• 关键词: Ablation; Acute; Adopted; Afferent Neurons; Age; Agonist; Anxiety; Apoptosis; Attention; Attentional deficit; Autonomic Dysfunction; Autophagocytosis; Blood Pressure; Brain; Brain Stem; Calcium; Cardiopulmonary; Cells; Chronic; Chronic Disease; Chronic Fatigue Syndrome; Clinical; Cognitive deficits; Computer software; Data; Demyelinations; Development; Disease; Disease model; Dizziness; Drops; Energy Metabolism; Exercise; Exercise Test; Exertion; Exhibits; FRAP1 gene; Fatigue; Female; Genes; Growth; Hand Strength; Heart Rate; Homeostasis; Impaired cognition; Impairment; Inflammation; Inflammatory; Investigation; Knock-out; Knockout Mice; Malaise; Measurement; Measures; Mental Depression; Metabolic; Mitochondria; Molecular; Molecular Analysis; Monitor; Mononuclear; Mouse Strains; Mus; Muscle; Muscle Fatigue; Muscle Weakness; Mutation; Myalgia; Neurocognitive Deficit; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Play; Production; Proteins; Protocols documentation; RANTES; Regimen; Role; Running; Spinal Cord; Spinal Ganglia; Spleen; Stress; Symptoms; System; Tamoxifen; Testing; Th1 Cells; Tissues; anaerobic glycolysis; brain cell; chronic inflammatory disease; knock-down; lymph nodes; motor impairment; mouse model; neural; novel; orthostatic intolerance; treadmill; Ablation; Acute; Adopted; Afferent Neurons; Age; Agonist; Anxiety; Apoptosis; Attention; Attentional deficit; Autonomic Dysfunction; Autophagocytosis; Blood Pressure; Brain; Brain Stem; Calcium; Cardiopulmonary; Cells; Chronic; Chronic Disease; Chronic Fatigue Syndrome; Clinical; Cognitive deficits; Computer software; Data; Demyelinations; Development; Disease; Disease model; Dizziness; Drops; Energy Metabolism; Exercise; Exercise Test; Exertion; Exhibits; FRAP1 gene; Fatigue; Female; Genes; Growth; Hand Strength; Heart Rate; Homeostasis; Impaired cognition; Impairment; Inflammation; Inflammatory; Investigation; Knock-out; Knockout Mice; Malaise; Measurement; Measures; Mental Depression; Metabolic; Mitochondria; Molecular; Molecular Analysis; Monitor; Mononuclear; Mouse Strains; Mus; Muscle; Muscle Fatigue; Muscle Weakness; Mutation; Myalgia; Neurocognitive Deficit; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Play; Production; Proteins; Protocols documentation; RANTES; Regimen; Role; Running; Spinal Cord; Spinal Ganglia; Spleen; Stress; Symptoms; System; Tamoxifen; Testing; Th1 Cells; Tissues; anaerobic glycolysis; brain cell; chronic inflammatory disease; knock-down; lymph nodes; motor impairment; mouse model; neural; novel; orthostatic intolerance; treadmill

Project summary: Myalgic encephalomyelitis and chronic fatigue syndrome (ME/CFS) is a multisystem chronic illness characterized by extreme fatigue, muscle weakness, muscle pain, dizziness, a cognitive deficit of attention, and depression. Despite intense investigation, the molecular mechanism of this disease is still unknown. Our recent finding suggests that the functional inactivation of ATG13, an essential protein of cellular autophagy, contributes to the pathogenesis of ME/CFS. To further characterize the role of ATG13 in the pathogenesis of ME/CFS, a reliable disease model is required that exhibits some of the cardinal disease symptoms such as post-exertional malaise (PEM) and orthostatic intolerance (OI). PEM is characterized by severe muscle fatigue and pains immediately after exercise, whereas OI is characterized by the sudden drop in blood pressure in an upright condition. Our preliminary results suggest that MHY1485, an agonist of mammalian target of rapamycin (mTOR), inactivates ATG13-dependent autophagy and induces severe fatigue and PEM in 3-4 weeks old female mice. Therefore, to establish the direct role of Atg13 in ME/CFS pathogenesis, our overall hypothesis is that atg13 depletion will display a spontaneous PEM pathology. In aim1, we will generate a mouse strain with muscle-specific knock-out of the atg13 gene (atg13∆muscle). A 20-minute acute treadmill running protocol and 2-days CPET tests would be adopted in these mice followed by simultaneous measurement of M- wave amplitude through EMG recording, decreased mobility recorded by Stoelting ANY-maze tracking software, muscle pain, stress, and neurocognitive impairment of attention (Aim 1.1). Molecular analysis of mitochondrial impairment in energy metabolism, calcium homeostasis, apoptosis, and anaerobic glycolysis would be evaluated in these mice (Aim 1.2). Under aim2, we would see if neural mutation of atg13 in myelinating cells of the brain (atg13∆brain) or ablation of atg13 in sensory neurons (atg13∆PNS) contributes to the pathogenesis of ME/CFS such as autonomic dysfunction, the cognitive deficit of attention, anxiety, and pain. Briefly, atg13∆brain and atg13∆PNS mice would be generated and then analyzed for chronic fatigue, followed by a 2-Days CPET test. After another 3-4 weeks, muscle fatigue, pain, stress, and neurocognitive impairment (aim 2.1) would be evaluated. Since chronic inflammation is one of the cardinal symptoms of ME/CFS, we would assess peripheral inflammation of CD4 Th1 cell activation in the spleen- and lymph node-derived mononuclear cells (Aim 2.2). Central inflammation will be assessed by monitoring the activation of NF-κB, iNOS, and RANTES production in the brain and spinal cord (Aim 2.2). If successful, our current proposal identifies the first mouse model to study ME/CFS and ME/CFS- associated PEM.

项目摘要：肌电脑脊髓炎和慢性疲劳综合征（ME/CFS）是多系统 慢性疾病的特征是极度疲劳，肌肉无力，肌肉疼痛，头晕，认知不足 注意和沮丧。尽管进行了激烈的研究，但该疾病的分子机制仍然是 未知。我们最近的发现表明ATG13的功能灭活是细胞的必要蛋白 自噬，有助于ME/CFS的发病机理。进一步表征ATG13在 ME/CFS的发病机理，需要一个可靠的疾病模型，该模型表现出一些基本疾病 诸如屈服后不适（PEM）和体位肠内（OI）之类的症状。 PEM的特征是 运动后立即严重的肌肉疲劳和疼痛，而OI的特征是突然下降 血压在直立状态。我们的初步结果表明Mhy1485，哺乳动物的激动剂 雷帕霉素（MTOR）的靶标，使ATG13依赖性自噬灭活，并引起严重的疲劳和PEM 3-4周大的雌鼠。因此，要确定ATG13在ME/CFS发病机理中的直接作用，我们的总体 假设是ATG13耗竭将显示出赞助的PEM病理学。在AIM1中，我们将产生一个 小鼠菌株与ATG13基因（ATG13ΔMUSCLE）的肌肉特异性敲除。一个20分钟的急性跑步机 这些小鼠将采用方案和2天CPET测试，然后简单地测量M- 通过EMG记录的波浪放大器，通过阻止任何迷恋跟踪软件记录的移动性降低， 注意力的肌肉疼痛，压力和神经认知障碍（AIM 1.1）。线粒体的分子分析 可以评估能量代谢，钙稳态，凋亡和厌氧性糖酵解的损害 在这些小鼠中（AIM 1.2）。在AIM2下，我们会看到大脑髓鞘细胞中ATG13的中性突变是否 （ATG13ΔBRAIN）或在感觉神经元中ATG13的消融（ATG13ΔPN）有助于ME/CFS的发病机理 作为自主功能障碍，注意力，焦虑和痛苦的认知不足。简而言之 将生成小鼠，然后分析慢性疲劳，然后进行2天CPET测试。另一个 将评估3-4周的肌肉疲劳，疼痛，压力和神经认知障碍（AIM 2.1）。自从 慢性炎症是ME/CFS的基本症状之一，我们将评估外周炎症 脾脏和淋巴结衍生的单核细胞中的CD4 TH1细胞活化（AIM 2.2）。中央炎症 将通过监测大脑和脊柱中NF-κB，iNOS和Rantes产生的激活来评估 电线（AIM 2.2）。如果成功，我们当前的建议将确定第一个研究ME/CFS和ME/CFS-的鼠标模型 相关的PEM。