ATG13: A new player in ME/CFS

ATG13：ME/CFS 的新玩家

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：肌痛性脑脊髓炎和慢性疲劳综合征（ME/CFS）是一个多系统疾病以极度疲劳、肌肉无力、肌肉疼痛、头晕、认知缺陷为特征的慢性疾病尽管进行了大量研究，但这种疾病的分子机制仍然存在。我们最近的发现表明细胞必需蛋白 ATG13 的功能失活。自噬有助于 ME/CFS 的发病机制进一步表征 ATG13 在 ME/CFS 中的作用。 ME/CFS 的发病机制，需要一个可靠的疾病模型来表现一些主要疾病诸如劳力后不适 (PEM) 和直立不耐受 (PEM) 等症状的特征是。运动后立即出现严重的肌肉疲劳和疼痛，而 OI 的特点是运动强度突然下降我们的初步结果表明，MHY1485 是哺乳动物的激动剂。雷帕霉素 (mTOR) 的靶点，使 ATG13 依赖性自噬失活，并在体内诱导严重疲劳和 PEM 因此，为了确定 Atg13 在 ME/CFS 发病机制中的直接作用，我们总体而言。假设 atg13 耗尽会表现出自发的 PEM 病理学，在 goal1 中，我们将生成一个。肌肉特异性敲除 atg13 基因 (atg13Δmuscle) 的小鼠品系 20 分钟的急性跑步机跑步。将在这些小鼠中采用方案和 2 天的 CPET 测试，然后同时测量 M- 通过 EMG 记录的波振幅，通过 Stoelting ANY-maze 跟踪软件记录的移动性下降，肌肉疼痛、压力和注意力的神经认知障碍（目标 1.1）。将评估能量代谢、钙稳态、细胞凋亡和无氧糖酵解的损害在这些小鼠中（目标 1.2），我们将观察大脑髓鞘细胞中 atg13 是否发生神经突变。 (atg13Δbrain) 或感觉神经元中 atg13 的消融 (atg13ΔPNS) 有助于 ME/CFS 的发病机制，例如简单来说，atg13Δbrain 和 atg13ΔPNS 是自主神经功能障碍、注意力、焦虑和疼痛的认知缺陷。将生成小鼠，然后对其进行慢性疲劳分析，然后进行为期 2 天的 CPET 测试。 3-4 周后，将评估肌肉疲劳、疼痛、压力和神经认知障碍（目标 2.1）。慢性炎症是 ME/CFS 的主要症状之一，我们将评估周围炎症脾脏和淋巴结来源的单核细胞中的 CD4 Th1 细胞激活（目标 2.2）。将通过监测大脑和脊髓中 NF-κB、iNOS 和 RANTES 生成的激活情况进行评估如果成功，我们当前的提案将确定第一个研究 ME/CFS 和 ME/CFS- 的小鼠模型。相关的PEM。