Oxidant Mediated Diaphragm Dysfunction in Diabetes

糖尿病中氧化剂介导的膈肌功能障碍

基本信息

批准号：
7210745
负责人：
LEIGH A CALLAHAN
金额：
$ 35.56万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7210745
关键词：
4-ethoxymethylene-2-phenyl-2-oxazoline-5-one Ablation Admission activity Angiotensin II Animal Model Animals Biochemical Biological Assay Calpain Caring Cell Culture Techniques Cell surface Cells Cessation of life Chemicals Complement Condition Contractile Proteins Coronary Arteriosclerosis Coronary Artery Bypass Critical Illness Data Databases Development Diabetes Mellitus Disease Electron Transport Endothelin-1 Environmental air flow Fiber Free Radical Scavengers Free Radicals Frequencies Functional disorder Gel Generations Genetic Techniques Glucose Goals Hand Health Hospitalization Hospitals Hyperglycemia In Situ In Vitro Incidence Injection of therapeutic agent Interleukins Ketones Kidney Diseases Knock-out Link Lipid Peroxidation Measures Mechanical ventilation Mediating Medical Medicare Membrane Mitochondria Morbidity - disease rate Mus Muscle Muscle Fibers Muscle Weakness Muscle function NADP NADPH Oxidase Neuropathy Nitric Oxide Synthase Numbers Operative Surgical Procedures Oxidants Oxygen Consumption Pathogenesis Pathway interactions Patients Performance Phosphorylation Physiological Postoperative Period Principal Investigator Process Production Protein Overexpression Protein Subunits Proteins Proteomics Pump Purpose Rate Rattus Research Research Design Research Personnel Respiratory Diaphragm Respiratory Failure Respiratory Muscles Respiratory System Respiratory Tract Infections Respiratory physiology Retinal Diseases Review Literature Risk Role Series Signal Transduction Skeletal Muscle Skin Source Streptozocin Structure Superoxide Dismutase Superoxides Techniques Testing Transgenic Animals Transgenic Organisms Up-Regulation Weaning Western Blotting Work Workload Xanthine Oxidase calpastatin chemical genetics diabetic hospital admission rate human AKAP13 protein improved inhibitor/antagonist mitochondrial dysfunction mortality non-diabetic novel therapeutics oxidation prevent programs protein function protein structure function research study respiratory response theories therapeutic target

项目摘要

Recent studies indicate that diabetes is associated with an increased incidence of respiratory failure, a heightened risk of postoperative respiratory complications, and a greater need for prolonged mechanical ventilation. However, it is not known how diabetes produces these problems. One potential explanation is that uncontrolled diabetes alters respiratory muscle function, reducing the capacity of the respiratory pump. The purpose of the present proposal is to examine this issue. Our central hypothesis is that poorly controlled diabetes induces severe free radical mediated diaphragm dysfunction. We will test this hypothesis in the following groups of studies. Aim I studies will characterize the effects of uncontrolled diabetes on diaphragm specific force generation, changes in muscle mass, and diaphragm endurance, testing the hypothesis diabetes induced alterations in diaphragm performance are related to increases in free radical generation. Aim II studies will interrogate a number of free radical generating pathways in muscle (including the cell surface NADPH oxidase) and determine which pathways are responsible for increased free radical generation in the diaphragm in diabetes. Aim III studies will determine if iNOS is upregulated in the diaphragm in diabetes, and will test the hypothesis that iNOS acts as an upstream modulator of free radical generation. Aim IV studies will examine several downstream targets of diabetes induced free radical generation in the diaphragm that are responsible for reductions in diaphragm performance, including contractile protein alterations, calpain mediated reductions in muscle mass, and alterations in mitochondrial ATP generating capacity. A variety of physiologic, biochemical, proteomic, fluorogenic, pharmacologic and genetic techniques will be used to test these hypotheses. Our preliminary data represent the first demonstration of upregulation of NADPH oxidase subunit proteins in skeletal muscle in any disease process, and suggest that iNOS regulates NADPH oxidase activity and free radical generation in the diaphragm in diabetes. These new data should provide important information regarding the pathogenesis of diabetes induced diaphragm dysfunction, and uncover pathways which could provide novel therapeutic targets for treatment of respiratory muscle weakness in this condition.

最近的研究表明，糖尿病与呼吸衰竭的发生率增加有关，呼吸衰竭是一种术后呼吸系统并发症的风险增加，并且更需要长时间的机械治疗通风。然而，尚不清楚糖尿病是如何产生这些问题的。一种可能的解释是不受控制的糖尿病会改变呼吸肌功能，降低呼吸泵的能力。本提案的目的是研究这个问题。我们的中心假设是控制不善糖尿病会引起严重的自由基介导的膈肌功能障碍。我们将在以下几组研究。目标 I 研究将描述不受控制的糖尿病对膈肌的影响比力的产生、肌肉质量的变化和膈肌耐力，检验假设糖尿病引起的膈肌性能改变与自由基产生的增加有关。 Aim II 研究将探究肌肉中的许多自由基生成途径（包括细胞表面 NADPH 氧化酶）并确定哪些途径导致自由基增加糖尿病患者膈肌中的生成。目标 III 研究将确定 iNOS 是否在糖尿病隔膜，并将检验 iNOS 作为自由基上游调节剂的假设一代。目标 IV 研究将检查糖尿病引起的自由基的几个下游靶点隔膜中产生的气体会导致隔膜性能下降，包括收缩蛋白改变、钙蛋白酶介导的肌肉质量减少以及线粒体的改变 ATP产生能力。各种生理学、生化、蛋白质组学、荧光、药理学和遗传技术将用于检验这些假设。我们的初步数据代表了第一个证明任何疾病过程中骨骼肌中 NADPH 氧化酶亚基蛋白的上调，并表明 iNOS 调节 NADPH 氧化酶活性和膈肌中自由基的产生糖尿病。这些新数据应该提供有关糖尿病发病机制的重要信息诱发膈肌功能障碍，并揭示可为该疾病提供新治疗靶点的途径治疗这种情况下的呼吸肌无力。