Metabolism, Skeletal Muscle, Cardiac Disease, Exercise

描述（由申请人提供）：候选人：候选人，John P. Konhilas博士，是一名研究助理，致力于扩大他在心血管生理学方面的广泛培训，以涵盖其他生物系统和及时的分子技术。Konhilas 1直接的职业目标是获得必要的研究和专业技能，以实现他的长期目标，即开发一个独立的、由校外资助的转化研究项目，重点是在心脏病状态和动物运动期间调节骨骼肌特征，因为它与人类疾病有关。拟议的K 01开发计划将为Konhilas博士提供额外的经验和培训，以实现这一目标。 职业发展计划：在奖励期间的培训活动包括，（1）获得新的和完善目前的研究技能，（2）结构化的活动，包括科学完整性，生物统计学课程，并出席/介绍杂志俱乐部，科学会议和指导互动。环境：Konhilas博士组建了一个导师团队，为提案的各个方面提供指导。Leslie Leinwand博士是一位得到了很好的校外资助的科学家和经过验证的导师。她为职业发展提供了一个富有成效和培养的研究环境。 调研：待检验的假设指出，骨骼肌的氧化能力在心脏病状态期间降低，并且可以通过运动训练恢复。为了研究关键代谢介质在这一过程中的作用，在心脏疾病进展和运动期间的特定时间，通过全身施用腺相关病毒（AAV）载体，将在骨骼肌中遗传破坏脂蛋白脂肪酶或过氧化物酶体增殖物激活受体α。在所有动物中，将分析骨骼肌的MyHC含量、肌纤维大小和氧化能力。 相关性：严重的骨骼肌无力和劳累时的疲劳是充血性心力衰竭（CHF）患者的主要临床特征。有氧运动可逆转CHF患者的运动不耐受，不依赖于中枢心脏效应。因此，确定心脏病、相关骨骼肌异常和运动之间的机制联系具有重要的临床意义。该提案将研究这种疾病过程的特定调节剂，并评估它们在疾病和运动恢复过程中的作用。

DESCRIPTION (provided by applicant): Candidate: The candidate, John P. Konhilas, Ph.D., is a research associate endeavoring to broaden his extensive training in cardiovascular physiology to encompass additional biological systems and timely molecular techniques. Dr. Konhilas1 immediate career goal is to acquire the research and professional skills necessary for achieving his long-term goal of developing an independent, extramurally-funded translational research program focusing on the regulation of skeletal muscle characteristics during cardiac disease states and exercise in animals as it relates to human disease. The proposed K01 development plan will provide Dr. Konhilas with the additional experience and training to achieve this goal. Career Development Plan: Training activities during the award period include, (1) acquiring new and refining present research skills, (2) structured activities including coursework in scientific integrity, biostatistics, and attendance/presentation at journal clubs, scientific meetings, and mentoring interactions. Environment: Dr. Konhilas has assembled a team of mentors to provide guidance in every facet of the proposal. The sponsor, Dr. Leslie Leinwand, is a well-established extramurally funded scientist and a proven mentor. She has provided a productive and nurturing research environment necessary for career development. Research: The hypothesis to be tested states that the oxidative capacity of skeletal muscle is reduced during cardiac disease states and can be recovered by exercise training. To examine the role of critical metabolic mediators in this process, lipoprotein lipase or peroxisome proliferator-activated receptor alpha will be genetically disrupted in skeletal muscle by systemic administration of adeno-associated viral (AAV) vectors at specific times during cardiac disease progression and exercise. In all animals, the skeletal muscles will be analyzed for MyHC content, muscle fiber size, and oxidative capacity. Relevance: Severe skeletal muscle weakness and fatigue upon exertion are major clinical features that occur in patients with congestive heart failure (CHF). The exercise intolerance can be reversed in CHF patients with aerobic exercise independent of central cardiac effects. Therefore, it is of major clinical significance that the mechanistic link be determined between cardiac disease, the associated abnormalities in skeletal muscle, and exercise. This proposal will examine specific regulators of this disease process and evaluate their role during disease and exercise recovery.