Mechanisms of Respiratory Muscle Dysfunction in Heart Failure

心力衰竭呼吸肌功能障碍的机制

基本信息

批准号：
7771050
负责人：
Leonardo Ferreira
金额：
$ 12.12万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7771050
关键词：
Acids Activities of Daily Living Address Affect Animals Area Arts Award Biochemistry Biology Biopsy Breathing Calcium Catalytic Domain Ceramides Chronic Clinical Clinical Sciences Complement Data Depressed mood Development Development Plans Doctor of Philosophy Elements Enrollment Event Exercise Exercise Tolerance Experimental Models Faculty Fatigue Fiber Functional disorder Future Generations Gills Goals Head Heart Heart failure Human Hypertension Impairment In Vitro Individual Institutes Intensive Care Units Intervention Interview Journals Kentucky Knock-out Laboratories Lipids Literature Measurement Measures Mechanical ventilation Mediating Mediation Mediator of activation protein Mental Depression Mentors Modeling Molecular Molecular Biology Molecular Biology Techniques Morbidity - disease rate Mus Muscle Muscle Cells Muscle Fibers Muscle Weakness Muscle function Myocardial Infarction NADPH Oxidase Operative Surgical Procedures Oxidants Oxidases Oxidative Stress Patients Peer Review Phase Phosphorylation Physical therapy Physiology Plasma Postdoctoral Fellow Process Production Protein Subunits Proteins Publishing Pulmonary Heart Disease Quality of life Reactive Oxygen Species Recombinants Recording of previous events Regulation Reporting Research Research Ethics Research Personnel Respiratory Diaphragm Respiratory Failure Respiratory Muscles Role Schools Science Scientist Second Messenger Systems Senior Scientist Serum Shortness of Breath Signal Transduction Skeletal Muscle Small Interfering RNA Sphingolipids Sphingomyelinase Staging Symptoms Testing Thoracic Surgical Procedures Training Translational Research Universities Vascular Endothelium Weaning Wild Type Mouse career career development cell type constriction design experience gp91ds-tat graduate student in vivo inhibitor/antagonist knockout gene meetings mortality novel oxidation performance site premature pressure prevent professor programs protein function public health relevance research study reuptake second messenger skills success therapy development

项目摘要

DESCRIPTION (provided by applicant): In patients with chronic heart failure (CHF) difficulty to breathe, and premature fatigue are the main symptoms limiting the patient's exercise tolerance, and ability to perform activities of daily life. During his clinical training the candidate treated several patients with CHF complaining of shortness of breath and fatigue. The candidate has a clinical background in physical therapy, and has been undergoing training (Ph.D. and postdoctoral) in the field of physiology to understand muscle weakness and fatigue. During this process the candidate has published 24 studies in peer-reviewed journals (13 first-author). The candidate's short-term goal is two-fold: to investigate the cellular and molecular mechanisms of respiratory muscle weakness and fatigue in heart failure; and ii) become an independent scientist. In the long-term the candidate's career goal is to become a tenured Professor heading a laboratory performing studies to understand mechanisms, and develop novel therapies to exercise intolerance experienced by patients with chronic cardiopulmonary diseases. As an independent investigator the candidate will have the rare expertise of applying discoveries at the cellular and molecular level to whole-body physiology, and bridge the gap between basic and clinical sciences. The research career development plan was designed to enhance the candidate's research skills and promote independence. The career development plan includes coursework in muscle physiology (relevant to respiratory muscle), molecular biology and cell signaling, and responsible conduct of research and ethics. These courses will complement the candidates training in clinical science, and whole-body/integrative physiology. Three senior scientists will mentor the candidate during the training component. These individuals have expertise in primary areas studied in the research plan (skeletal muscle physiology, sphingolipid biology, and respiratory failure and translational science). In addition to interacting with each mentor individually, the candidate and all mentors will meet to discuss research findings, plan future directions, and evaluate progress. The mentors will also assist directly in the transition to independence by performing mock faculty-search interviews, and discussing negotiation strategies. The project performance site is the University of Kentucky (U.K.). The Center for Muscle Biology and Gill Heart Institute are part of U.K. and key to the success of the candidate's training. The laboratory of mentors and collaborators can provide the support necessary to complete the mentored phase of this award. Most individuals involved in the project are faculty in the candidate's and primary mentor's department (Dept. of Physiology). All mentors and collaborators are leaders in their field of research, and have trained graduate students and post-docs. Courses proposed are offered as part of the U.K. Integrated Biomedical Sciences Graduate Program, and the candidate has been admitted to the U.K. Graduate School and will readily enroll for courses when this award is made. Respiratory muscle weakness contributes to the morbidity and mortality of patients with CHF. Published reports show that increased plasma sphingomyelinase (SMase) activity is associated with muscle weakness in CHF patients. Our preliminary data suggest that SMase mimics the effect of CHF on the diaphragm (i.e., oxidative stress and weakness). It appears that SMase mediates diaphragm weakness through activation of NAD(P)H oxidase that leads to oxidative stress. Oxidative stress impairs calcium regulation and the function of the contractile apparatus. The research plan was designed to elucidate the mechanisms of respiratory muscle weakness and fatigue in CHF. To accomplish this goal we will address three specific aims: Aim 1. To identify intramyocyte mechanisms mediating diaphragm muscle dysfunction in CHF. Aim 2. To define SMase as a mediator of diaphragm muscle dysfunction in CHF. Aim 3: To test the role of NAD(P)H oxidase on diaphragm muscle dysfunction of CHF mice. PUBLIC HEALTH RELEVANCE: NARRATIVE Patients with heart failure due to, for example, heart attack or long history of high blood pressure have weakness of the respiratory muscles that contribute to shortness of breath. The goal of this project is to identify the key mechanisms that cause respiratory muscle dysfunction in heart failure. This will facilitate the development of new therapies to prevent weakness and fatigue of the respiratory muscles in patients with heart failure. Improvement of the respiratory muscle function should increase the patient's ability to perform daily tasks, and enhance quality of life.

描述（由申请人提供）：在慢性心力衰竭（CHF）难以呼吸的患者中，过早的疲劳是限制患者运动耐受性和进行日常生活活动的能力的主要症状。在他的临床培训中，候选人治疗了几名CHF患者，抱怨呼吸急促和疲劳。该候选人具有物理治疗的临床背景，并且一直在生理学领域接受培训（博士学位和博士后），以了解肌肉无力和疲劳。在此过程中，候选人在同行评审期刊上发表了24项研究（13位第一任作者）。候选人的短期目标是两个方面：研究心力衰竭中呼吸道肌肉无力和疲劳的细胞和分子机制； ii）成为独立科学家。从长远来看，候选人的职业目标是成为一名终身教授，负责实验室进行研究，以了解机制，并开发新的疗法，以行使慢性心肺疾病患者经历的不宽容。作为一名独立研究者，候选人将具有罕见的专业知识，即在细胞和分子水平上将发现应用于全身生理学，并弥合基础科学和临床科学之间的差距。研究职业发展计划旨在提高候选人的研究技能并促进独立性。职业发展计划包括肌肉生理学课程（与呼吸肌肉有关），分子生物学和细胞信号传导以及负责任的研究和伦理。这些课程将补充临床科学和全身/综合生理学的候选人培训。三名高级科学家将在培训部分指导候选人。这些人在研究计划中研究的初级领域（骨骼肌生理，鞘脂生物学，呼吸衰竭和转化科学）具有专业知识。除了单独与每个导师互动外，候选人和所有导师还将开会以讨论研究结果，计划未来的方向并评估进度。导师还将通过进行模拟教师搜索访谈并讨论谈判策略，直接帮助过渡到独立性。项目绩效网站是肯塔基大学（英国）。肌肉生物学和吉尔心脏研究所中心是英国的一部分，也是候选人培训成功的关键。导师和合作者的实验室可以提供必要的支持，以完成该奖项的指导阶段。参与该项目的大多数人是候选人和主要导师部（生理学系）的教师。所有导师和合作者都是研究领域的领导者，并且已经培训了研究生和培训。提议的课程是英国综合生物医学研究生课程的一部分，候选人已被录取给英国研究生院，并在获得该奖项时很容易入学。呼吸道肌肉无力有助于CHF患者的发病率和死亡率。发表的报告显示，血浆鞘磷脂酶（SMASE）活性增加与CHF患者的肌肉无力有关。我们的初步数据表明，SMASE模拟了CHF对隔膜的影响（即氧化应激和无力）。似乎Smase通过激活NAD（P）H氧化酶的激活来介导diaphragm弱的弱点，而NAD（P）H氧化酶会导致氧化应激。氧化应激会损害钙调节和收缩设备的功能。该研究计划旨在阐明CHF中呼吸道肌肉无力和疲劳的机制。为了实现这一目标，我们将解决三个具体目标：目标1。确定介导CHF中隔膜肌肉功能障碍的加压细胞内机制。目标2。将SMASE定义为CHF中diaphragm肌功能障碍的介体。目标3：测试NAD（P）H氧化酶对CHF小鼠的diaphragm肌肉功能障碍的作用。公共卫生相关性：由于心脏病发作或高血压史而导致的心力衰竭的叙事患者的呼吸肌肉无力导致呼吸急促。该项目的目的是确定引起心力衰竭呼吸肌功能障碍的关键机制。这将有助于开发新疗法，以防止心力衰竭患者的呼吸肌肉无力和疲劳。呼吸肌功能的改善应提高患者执行日常任务的能力，并提高生活质量。