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：
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
项目类别：
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

项目摘要

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.

抽象的慢性心力衰竭 (CHF) 患者的主要症状是呼吸困难和过早疲劳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抱怨呼吸急促和疲劳的慢性心力衰竭患者。候选人具有物理治疗的临床背景，并一直在接受物理治疗方面的培训（博士和博士后）生理学领域了解肌肉无力和疲劳。在此过程中，候选人已在同行评审期刊上发表了 24 篇研究（13 篇为第一作者）。候选人的短期目标有两个：研究心力衰竭呼吸肌无力和疲劳的细胞和分子机制； ii) 成为一名独立科学家。从长远来看，候选人的职业目标是成为终身教授教授领导一个实验室进行研究以了解机制并开发新疗法慢性心肺疾病患者的运动不耐受。作为一个独立的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。职业发展计划包括肌肉生理学课程（与呼吸相关）肌肉）、分子生物学和细胞信号传导，以及负责任的研究行为和道德规范。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。这些人拥有以下方面的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）。除了与每位导师单独互动之外，候选人和所有人导师将开会讨论研究结果、规划未来方向并评估进展。导师们将还通过进行模拟教师招聘面试来直接协助向独立的过渡，以及讨论谈判策略。项目表演地点是肯塔基大学（英国）。肌肉生物学和鳃心中心该学院是英国的一部分，是候选人培训成功的关键。导师和实验室合作者可以提供完成该奖项的指导阶段所需的支持。最多参与该项目的个人是候选人和主要导师所在部门（系）的教师。生理）。所有导师和合作者都是其研究领域的领导者，并拥有经过培训的研究生学生和博士后。提议的课程作为英国综合生物医学科学的一部分提供研究生课程，并且候选人已被英国研究生院录取，并且可以轻松注册颁发此奖项时的课程。呼吸肌无力会导致CHF患者的发病率和死亡率。已发表报告显示血浆鞘磷脂酶 (SMase) 活性增加与肌肉无力有关慢性心力衰竭患者。我们的初步数据表明 SMase 模拟了 CHF 对隔膜的影响（即，氧化应激和虚弱）。 SMase 似乎通过激活 NAD(P)H 氧化酶会导致氧化应激。氧化应激损害钙调节和功能收缩装置。该研究计划旨在阐明呼吸肌的机制 CHF 患者的虚弱和疲劳。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 膈肌功能障碍的肌细胞内机制。目标 2. 将 SMase 定义为 CHF 膈肌功能障碍的介质。目标 3：测试 NAD(P)H 氧化酶对隔膜的作用 CHF 小鼠的肌肉功能障碍。