Mechanisms of Respiratory Muscle Dysfunction in Heart Failure

描述(申请人提供)：在慢性心力衰竭(CHF)患者中，呼吸困难和过早疲劳是限制患者运动耐量和进行日常生活活动能力的主要症状。在他的临床培训期间，这位候选人治疗了几名CHF患者，他们抱怨呼吸急促和疲劳。应聘者有物理疗法的临床背景，并一直在接受生理学领域的培训(博士和博士后)，以了解肌肉无力和疲劳。在这一过程中，候选人在同行评议的期刊上发表了24篇研究(第一作者13篇)。候选人的短期目标有两个：研究心力衰竭中呼吸肌无力和疲劳的细胞和分子机制；ii)成为一名独立的科学家。从长远来看，候选人的职业目标是成为一名终身教授，领导实验室进行研究以了解机制，并开发新的疗法来治疗慢性心肺疾病患者经历的运动不耐受。作为一名独立的研究人员，候选人将拥有将细胞和分子水平的发现应用于全身生理学的罕见专业知识，并弥合基础科学和临床科学之间的差距。研究生涯发展计划旨在提高应聘者的研究技能和促进独立性。职业发展计划包括肌肉生理学(与呼吸肌相关)、分子生物学和细胞信号转导方面的课程，以及负责任的研究和伦理行为。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。三名资深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主要领域(骨骼肌生理学、鞘脂生物学、呼吸衰竭和翻译科学)拥有专业知识。除了单独与每位导师互动外，候选人和所有导师还将会面，讨论研究结果，规划未来方向，并评估进展。导师还将通过进行模拟教师面试和讨论谈判策略，直接协助向独立的过渡。该项目的执行地点是肯塔基大学(英国)。肌肉生物学中心和鳃心脏研究所是英国的一部分，也是候选人培训成功的关键。导师和合作者实验室可以提供必要的支持，以完成该奖项的导师阶段。参与该项目的大多数人都是候选人和初级导师系(系)的教职员工。生理学)。所有导师和合作者都是各自研究领域的领导者，并培养过研究生和博士后。所建议的课程是作为英国综合生物医学研究生项目的一部分提供的，候选人已被英国研究生院录取，并将在该奖项颁发时随时报读课程。呼吸肌无力是CHF患者发病和死亡的重要原因。已发表的报告表明，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对横隔膜的影响(即氧化应激和虚弱)。看来，sMase通过激活NAD(P)H氧化酶而导致氧化应激，从而介导了横隔膜的虚弱。氧化应激损害钙调节和收缩装置的功能。该研究计划旨在阐明CHF患者呼吸肌无力和疲劳的机制。为了实现这一目标，我们将致力于三个具体目标：目标1.确定CHF患者横隔肌功能障碍的细胞内机制。目的2.将sMase定义为充血性心力衰竭(CHF)时隔肌功能障碍的介质。目的：探讨NAD(P)H氧化酶在慢性心力衰竭小鼠膈肌功能障碍中的作用。 公共卫生相关性：叙述性患者由于心脏病发作或长期高血压病史而导致心力衰竭，他们的呼吸肌无力导致呼吸短促。该项目的目标是确定导致心力衰竭时呼吸肌功能障碍的关键机制。这将有助于开发新的治疗方法，以防止心力衰竭患者呼吸肌的虚弱和疲劳。呼吸肌功能的改善应提高患者执行日常任务的能力，提高生活质量。

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.