In patients with chronic heart failure (CHF) difficulty to breathe, and premature fatigue are the main symptomslimiting the patient's exercise tolerance, and ability to perform activities of daily life. During his clinical trainingthe candidate treated several patients with CHF complaining of shortness of breath and fatigue. The candidatehas a clinical background in physical therapy, and has been undergoing training (Ph.D. and postdoctoral) in thefield of physiology to understand muscle weakness and fatigue. During this process the candidate haspublished 24 studies in peer-reviewed journals (13 first-author). The candidate's short-term goal is two-fold: toinvestigate 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 tenuredProfessor heading a laboratory performing studies to understand mechanisms, and develop novel therapies toexercise intolerance experienced by patients with chronic cardiopulmonary diseases. As an independentinvestigator the candidate will have the rare expertise of applying discoveries at the cellular and molecular levelto 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 promoteindependence. The career development plan includes coursework in muscle physiology (relevant to respiratorymuscle), molecular biology and cell signaling, and responsible conduct of research and ethics. These courseswill complement the candidates training in clinical science, and whole-body/integrative physiology. Threesenior scientists will mentor the candidate during the training component. These individuals have expertise inprimary areas studied in the research plan (skeletal muscle physiology, sphingolipid biology, and respiratoryfailure and translational science). In addition to interacting with each mentor individually, the candidate and allmentors will meet to discuss research findings, plan future directions, and evaluate progress. The mentors willalso assist directly in the transition to independence by performing mock faculty-search interviews, anddiscussing negotiation strategies.The project performance site is the University of Kentucky (U.K.). The Center for Muscle Biology and Gill HeartInstitute are part of U.K. and key to the success of the candidate's training. The laboratory of mentors andcollaborators can provide the support necessary to complete the mentored phase of this award. Mostindividuals involved in the project are faculty in the candidate's and primary mentor's department (Dept. ofPhysiology). All mentors and collaborators are leaders in their field of research, and have trained graduatestudents and post-docs. Courses proposed are offered as part of the U.K. Integrated Biomedical SciencesGraduate Program, and the candidate has been admitted to the U.K. Graduate School and will readily enroll forcourses when this award is made.Respiratory muscle weakness contributes to the morbidity and mortality of patients with CHF. Publishedreports show that increased plasma sphingomyelinase (SMase) activity is associated with muscle weakness inCHF 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 ofNAD(P)H oxidase that leads to oxidative stress. Oxidative stress impairs calcium regulation and the function ofthe contractile apparatus. The research plan was designed to elucidate the mechanisms of respiratory muscleweakness and fatigue in CHF. To accomplish this goal we will address three specific aims:
Aim 1. To identifyintramyocyte mechanisms mediating diaphragm muscle dysfunction in CHF.
Aim 2. To define SMase as amediator of diaphragm muscle dysfunction in CHF.
Aim 3 : To test the role of NAD(P)H oxidase on diaphragmmuscle dysfunction of CHF mice.
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.
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