Nox2-Calcium Signaling in Skeletal Muscle

骨骼肌中的 Nox2-钙信号传导

基本信息

批准号：
8707972
负责人：
George G Rodney
金额：
$ 34.51万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707972
关键词：
Address Animal Model Biological Calcium Calcium Signaling Cells Coupling Cytosol Data Development Disease Dominant-Negative Mutation Electric Stimulation Exercise Fatigue Foundations Functional disorder Generations Goals Green Fluorescent Proteins HIV Heart failure Homeostasis Isometric Exercise Knockout Mice Life Link Malignant Neoplasms Measurement Measures Mechanical Stress Membrane Mitochondria Multienzyme Complexes Mus Muscle Muscle Contraction Muscle Fatigue Muscle Fibers Muscle Weakness Muscle function Muscular Dystrophies Myopathy Myosin ATPase NADPH Oxidase Oxidation-Reduction Oxidative Stress Pathway interactions Patients Performance Phosphorylation Physiological Play Process Production Pulmonary Emphysema Reactive Oxygen Species Regulation Research Research Project Grants Role Scientist Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Site Skeletal Muscle Specific qualifier value Staging Stretching Testing Triad Acrylic Resin Work antioxidant therapy base combat feeding flexor digitorum brevis inhibitor/antagonist novel oxidation prevent public health relevance research study response sensor spatiotemporal src-Family Kinases tool

项目摘要

DESCRIPTION (provided by applicant): Generation of reactive oxygen species (ROS) under physiological conditions is required for normal force production in skeletal muscle. However, high levels of ROS are observed during intense physical exercise and promote contractile dysfunction, resulting in muscle weakness and fatigue. There is growing evidence that sub-cellular site-specific ROS production governs the beneficial vs. damaging effects of ROS. NADPH oxidase (Nox2) is an enzyme complex that generates ROS. Ongoing work by PI has found that increased ROS generation from Nox2 during intense contractile activity contributes to fatigue. We have strong evidence that Src tyrosine kinase acts as a redox switch to activate Nox2. The central hypothesis of this proposal is that Nox2 and Src act through a feed-forward pathway leading to excessive ROS production and contractile dysfunction. We will use genetically modified mice lacking Nox2, genetically encoded site-specific redox sensors and a novel tool to measure force and Ca2+ transients simultaneously in living skeletal muscle fibers to address the following specific aims: 1. Define the mechanisms by which contractile activity increases Nox2 dependent ROS production in skeletal muscle, 2. Determine whether Src serves as a redox switch to modulate activity dependent ROS production, and 3. Assess the role of Nox2 and Src on cytosolic [Ca2+ ]i transients and force generation. The proposed research will identify the sub-cellular sites of ROS production and elucidate the signaling pathways that control ROS regulation of microdomain Ca2+ signaling in skeletal muscle. Furthermore, it will lay the foundation for the development of targeted antioxidant therapy to combat the deleterious effects of overproduction of ROS seen in muscle fatigue and disease.

描述（由申请人提供）：在生理条件下产生活性氧（ROS）的产生是骨骼肌中的正常力量产生。但是，在强烈的体育锻炼中观察到高水平的ROS并促进收缩功能障碍，导致肌肉无力和疲劳。越来越多的证据表明，亚细胞特异性ROS的产生控制ROS的有益和破坏性影响。 NADPH氧化酶（NOX2）是产生ROS的酶复合物。 PI正在进行的工作发现，在强烈的收缩活动期间，NOX2的ROS产生增加会导致疲劳。我们有强有力的证据表明SRC酪氨酸激酶是激活NOX2的氧化还原转换。该提案的中心假设是NOX2和SRC通过饲养前途径起作用，导致ROS产生过多和收缩功能障碍。我们将使用缺乏NOX2，遗传编码的特定氧化还原传感器的遗传改性小鼠，以及在生存的骨骼肌纤维中同时测量力和Ca2+瞬态的新型工具来解决以下特定目的：1。定义机制，通过哪种收缩活动会增加NOX2依赖性的生产，从而依赖于Skelet sectient of Skelet sectiont skeled as selt oss src src src src。 3。评估NOX2和SRC在胞质[Ca2+] I瞬变和力产生中的作用。拟议的研究将确定ROS产生的亚细胞位点，并阐明控制骨骼肌中微域Ca2+信号传导ROS调节的信号通路。此外，它将为靶向抗氧化剂疗法的发展奠定基础，以应对在肌肉疲劳和疾病中看到的ROS过量产生的有害影响。