Mechanisms of Respiratory Muscle Dysfunction in Heart Failure

心力衰竭呼吸肌功能障碍的机制

• 批准号: 8331531
• 负责人: Leonardo Ferreira
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331531
• 关键词: Activities of Daily Living; Address; Affect; Animals; Area; Award; Basic Science; 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 Fatigue; Muscle Fibers; Muscle Weakness; Muscle function; Myocardial Infarction; NADPH Oxidase; Niemann-Pick Diseases; 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; acid sphingomyelinase; 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; research study; reuptake; second messenger; skills; success; therapy development

ABSTRACT 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.

摘要 慢性心力衰竭（CHF）患者呼吸困难、过早疲劳是主要症状 限制患者的运动耐量和进行日常生活活动的能力。在他的临床训练期间 该候选人治疗了几名主诉呼吸短促和疲劳的CHF患者。候选 具有物理治疗的临床背景，并一直在接受培训（博士，和博士后）， 了解肌肉无力和疲劳的生理学领域。在此过程中，候选人必须 在同行评审期刊上发表了24项研究（13名第一作者）。候选人的短期目标是双重的： 探讨心力衰竭时呼吸肌无力和疲劳的细胞和分子机制; 2.成为独立的科学家。从长远来看，候选人的职业目标是成为终身职位 教授领导一个实验室进行研究，以了解机制，并开发新的疗法， 慢性心肺疾病患者的运动不耐受。作为一个独立 研究员候选人将拥有在细胞和分子水平上应用发现的罕见专业知识 到全身生理学，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， 独立职业发展计划包括肌肉生理学课程（与呼吸系统相关） 肌肉），分子生物学和细胞信号，以及负责任的研究和道德行为。这些课程 将补充候选人在临床科学和全身/综合生理学方面的培训。三 资深科学家将在培训期间指导候选人。这些人有专业知识， 研究计划中研究的主要领域（骨骼肌生理学、鞘脂生物学和呼吸系统 失败和转化科学）。除了与每个导师单独互动外，候选人和所有 导师将会面讨论研究结果，规划未来方向，并评估进展。导师们将 还通过模拟院系搜索面试直接帮助过渡到独立， 讨论谈判策略 项目执行地点为英国肯塔基州大学。肌肉生物学和鳃心脏中心 研究所是英国的一部分。也是候选人培训成功的关键导师实验室， 合作者可以提供必要的支持，以完成该奖项的指导阶段。最 参与该项目的个人是候选人和主要导师所在系的教员。的 生理学）。所有导师和合作者都是各自研究领域的领导者，并培养了研究生 学生和博士后。建议的课程是作为联合王国的一部分提供的。综合生物医学科学 研究生课程，并且候选人已被英国录取。研究生院，并将随时报名参加 当这个奖项被授予时。 呼吸肌无力导致CHF患者的发病率和死亡率。发表 有报道表明，血浆鞘磷脂酶（SMase）活性增加与肌肉无力有关， CHF患者。我们的初步数据表明，SMase模拟CHF对隔膜的影响（即， 氧化应激和虚弱）。SMase似乎通过激活 NAD（P）H氧化酶，导致氧化应激。氧化应激损害钙调节和 收缩器官本研究旨在阐明呼吸肌的作用机制 CHF中的虚弱和疲劳。为了实现这一目标，我们将提出三个具体目标：目标1。以识别 CHF中介导膈肌功能障碍的肌细胞内机制目标2.要将SMase定义为 CHF中膈肌功能障碍的介质。目的3：探讨膈肌NAD（P）H氧化酶的作用 CHF小鼠的肌肉功能障碍。