Mechanisms of Respiratory Muscle Dysfunction in Heart Failure

摘要 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 这位候选人治疗了几名主诉呼吸急促和疲劳的CHF患者。候选人 有物理治疗的临床背景，并一直在接受博士和博士后培训 了解肌肉无力和疲劳的生理学领域。在这个过程中，候选人有 在同行评议期刊上发表了24篇研究(第一作者13篇)。候选人的短期目标有两个： 探讨心力衰竭时呼吸肌无力和疲劳的细胞和分子机制； 和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职 领导实验室的教授进行研究以了解机制，并开发新的治疗方法 慢性心肺疾病患者经历的运动不耐受。作为一个独立的 研究人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 走向全身生理学，弥合基础科学和临床科学之间的鸿沟。 研究职业发展计划旨在提高应聘者的研究技能并促进 独立。职业发展计划包括肌肉生理学(与呼吸相关)的课程 (肌肉)、分子生物学和细胞信号，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 资深科学家将在培训部分指导候选人。这些人在以下方面具有专业知识 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 失败和翻译科学)。除了与每个导师单独互动外，候选人和所有 导师们将开会讨论研究结果，规划未来方向，并评估进展情况。导师们将会 还通过进行模拟教员搜索面试，直接协助向独立的过渡，以及 讨论谈判策略。 该项目的执行地点是肯塔基大学(英国)。肌肉生物学和鳃心脏研究中心 学院是英国的一部分，是候选人培训成功的关键。导师和导师的实验室 合作者可以提供必要的支持，以完成本奖项的指导阶段。多数 参与该项目的个人是候选人所在系和初级导师系(系)的教师。的 生理学)。所有的导师和合作者都是各自研究领域的领导者，并且都培养过毕业生。 学生和博士后。建议的课程是作为英国综合生物医学科学的一部分提供的 研究生课程，应聘者已被英国研究生院录取，并将随时报名参加 当这一奖项颁发时，课程。 呼吸肌无力是CHF患者发病和死亡的重要原因。已出版 报告显示，血浆鞘磷脂酶(SMase)活性增加与肌肉无力有关 充血性心力衰竭患者。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)。SMase似乎是通过激活一种新的肌动蛋白 导致氧化应激的NAD(P)H氧化酶。氧化应激损害钙调节和钙调素的功能 收缩装置。该研究计划旨在阐明呼吸肌的作用机制。 充血性心力衰竭的虚弱和疲劳。为了实现这一目标，我们将实现三个具体目标：目标1.确定 充血性心力衰竭患者横隔肌功能障碍的细胞内机制。目标2.将sMase定义为 充血性心力衰竭时横隔肌功能障碍的介体。目的3：检测NAD(P)H氧化酶在横隔膜上的作用 慢性心力衰竭小鼠的肌肉功能障碍。

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.