权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Respiratory Muscle Weakness in Chronic Inflammation

慢性炎症导致的呼吸肌无力

基本信息

批准号：
8446919
负责人：
Francisco H Andrade
金额：
$ 26.55万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446919
关键词：
Address Animal Model Animals Antioxidants Arachidonic Acids Area Binding Biological Assay Breathing Calcium Cardiovascular Diseases Cell Culture Techniques Ceramides Chronic Chronic Disease Chronic Obstructive Airway Disease Clinical Complement Data Depressed mood Disease Dyspnea Esthesia Event Exercise Exercise Tolerance Extracellular Signal Regulated Kinases Fiber Functional disorder Genetic Goals Health Heart failure Hour Human Inflammation Inflammatory Intervention Lead Life Ligand Binding Link MAPK3 gene Mediating Mediator of activation protein Microfilaments Mitochondria Morbidity - disease rate Muscle Muscle Fibers Muscle Weakness Muscle function Neurons Nitric Oxide Synthase Oxidants Oxidation-Reduction Pathway interactions Patients Peroxonitrite Phospholipase Phospholipase A2 Phosphotransferases Physiologic intraventricular pressure Post-Translational Protein Processing Production Protein Isoforms Protein Kinase Proteins Publishing Pulmonary Emphysema Reactive Oxygen Species Research Respiratory Diaphragm Respiratory Failure Respiratory Muscles Role Serum Signal Transduction Source Sphingolipids Sphingomyelinase Symptoms Testing Therapeutic Agents Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Work drug development gene therapy mortality mouse model muscle strength novel premature pressure prevent receptor research study response therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify therapies that will preserve diaphragm function in chronic inflammatory conditions including heart failure and chronic obstructive pulmonary disease. Our current focus is loss of specific force in diaphragm which promotes exercise intolerance, breathlessness, and respiratory failure. A promising therapeutic target is tumor necrosis factor (TNF). TNF serum levels are elevated in chronic disease, correlate with muscle weakness, and are a predictor of morbidity and mortality. TNF depresses contractile function of diaphragm and stimulates oxidant production by diaphragm muscle fibers. The oxidants appear to cause weakness since interventions that limit oxidant activity prevent loss of force. Our central hypothesis is that respiratory muscle function can be preserved in chronic inflammatory disease by inhibiting TNF receptor-mediated effects on diaphragm muscle fibers. This project will define signaling events and redox mechanisms by which TNF depresses force and will evaluate pharmacologic and genetic interventions to preserve diaphragm function. We also will evaluate pathophysiologic relevance, defining the role of TNF in a mouse model of disease and testing the capacity of clinical therapeutic agents to preserve diaphragm function. The project addresses three specific aims: Aim 1. To evaluate sphingolipid signaling as an early post-receptor mechanism by which TNF/TNFR1 stimulates oxidant activity and weakness. Cell culture studies will assess sphingomyelinase activation and ceramide-sensitive signaling events downstream of the TNF receptor subtype 1. Aim 2. To assess the source, composition, and post-translational target of oxidants that mediate TNF-stimulated weakness. Diaphragm fiber bundles and isolated mitochondria will be used to define ROS and NO contributions via redox assays and pharmacologic and genetic tools. Aim 3. To test TNF signaling as a contributor to respiratory muscle weakness in heart failure and a potential target for therapy. An animal model of heart failure will be used to define the diaphragm response to chronic inflammation, to test TNF as a systemic mediator, and to evaluate potential therapies that are approved for use in humans.

描述（由申请人提供）：本项目的长期目标是确定在慢性炎症性疾病（包括心力衰竭和慢性阻塞性肺疾病）中保护膈肌功能的疗法。我们目前的重点是膈肌的比力损失，这会导致运动不耐受、呼吸困难和呼吸衰竭。肿瘤坏死因子（TNF）是一个有前途的治疗靶点。TNF血清水平在慢性疾病中升高，与肌无力相关，并且是发病率和死亡率的预测因子。TNF抑制膈肌的收缩功能并刺激膈肌纤维产生氧化剂。氧化剂似乎会导致虚弱，因为限制氧化剂活性的干预措施可以防止力量的损失。我们的中心假设是，在慢性炎症性疾病中，通过抑制TNF受体介导的对膈肌纤维的作用，可以保护呼吸肌功能。该项目将定义信号事件和氧化还原机制，TNF抑制力，并将评估药理学和遗传干预措施，以保持隔膜功能。我们还将评估病理生理相关性，确定肿瘤坏死因子在小鼠疾病模型中的作用，并测试临床治疗药物保护膈肌功能的能力。该项目针对三个具体目标：目标1。评估鞘脂信号传导作为TNF/TNFR 1刺激氧化活性和虚弱的早期受体后机制。细胞培养研究将评估TNF受体亚型1下游的鞘磷脂酶活化和神经酰胺敏感性信号传导事件。目标二。评估介导TNF刺激的虚弱的氧化剂的来源、组成和翻译后靶点。隔膜纤维束和分离的线粒体将用于通过氧化还原测定以及药理学和遗传学工具来定义ROS和NO贡献。目标3。测试TNF信号作为心力衰竭中呼吸肌无力的贡献者和潜在的治疗靶点。心力衰竭的动物模型将用于定义膈肌对慢性炎症的反应，以测试TNF作为全身介质，并评估批准用于人类的潜在疗法。