Androgens and Myocardial Relaxation in the Aging Heart

描述（由申请人提供）：本提案旨在支持医学博士西奥多亚伯拉罕的职业发展，马约医学院的内科助理教授。申请人的职业目标是开发一个独立的，动态的，转化的研究计划，整合创新的成像方式和肌肉生理学，在一个充满活力和刺激的科学环境。KO 8奖将保护申请人的临床职责，如超声心动图实验室的人员配备，并允许全职研究。申请人计划加强正在进行的临床研究，并在资深研究人员的指导下，提高他的专业知识，并在肌肉生理学，内分泌学和衰老方面获得独立性。这项提案的科学目标是研究睾酮在年龄相关性舒张功能障碍发展中的作用。衰老与舒张功能障碍有关，舒张功能障碍导致老年人的显著发病率和死亡率。由于睾酮水平随着年龄的增长而下降，因此假设睾酮缺乏形成舒张功能障碍发展的病理生理基础，并且睾酮替代加重老年人的舒张功能障碍。使用创新的成像技术，申请人最近引入了在年龄相关的舒张功能障碍中具有明显意义的新概念。本提案旨在扩展这些观察结果，并计划：a）在NIH资助的随机、双盲、安慰剂对照临床研究中（申请人为心血管部分的项目负责人），检测睾酮缺乏是否会导致老年人的舒张功能障碍，以及睾酮替代品的使用; B）在相同的环境中，检查睾酮是否通过调节外周血流动力学介导舒张功能;和c）在动物模型中，探索睾酮介导的舒张功能障碍的可能潜在细胞机制，特别是细胞内钙调节。拟议的实验将产生重要的新知识，与年龄相关的舒张功能障碍，特别是关于激素变化和心室力学之间的相互作用。最重要的是，这项研究的潜在直接临床益处包括早期发现，改进和新颖的治疗，以及年龄相关舒张功能障碍的更好临床结局。

DESCRIPTION (provided by applicant): This proposal seeks to support the career development of Theodore Abraham, M.D., an Assistant Professor of Internal Medicine at the Mayo Medical School. The applicant's career goal is to develop an independent, dynamic, translational research program, integrating innovative imaging modalities and muscle physiology, within a vibrant and stimulating scientific environment. The KO8 award would protect the applicant from clinical duties, such as staffing the echocardiography laboratory, and allow full time research. The applicant plans to strengthen ongoing clinical research, and enhance his expertise and gain independence in muscle physiology, endocrinology and aging, under the mentorship of senior, established investigators. The scientific goal of this proposal is to examine the role of testosterone in the development of age-related diastolic dysfunction. Aging is associated with diastolic dysfunction that results in significant morbidity and mortality in the elderly. Since testosterone levels decrease with age, it is hypothesized that testosterone deficiency forms the pathophysiologic basis for the development of diastolic dysfunction, and that testosterone replacement alleviates diastolic dysfunction in the elderly. Using innovative imaging techniques, the applicant has recently introduced novel concepts with obvious implications in age-related diastolic dysfunction. This proposal seeks to expand on these observations, and plans to: a) in the setting of a NIH funded, randomized, double-blind, placebo-controlled clinical study (applicant is the project leader for the cardiovascular component), test whether testosterone deficiency worsens, and replacement alleviates, diastolic dysfunction in the elderly; b) in the same setting, examine whether testosterone mediates diastolic function through regulation of peripheral hemodynamics; and c) in an animal model, explore possible underlying cellular mechanisms of testosterone-mediated diastolic dysfunction, specifically intracellular calcium regulation. The proposed experiments will generate significant new knowledge pertaining to age-related diastolic dysfunction, specifically with regard to the interactions between hormonal changes and ventricular mechanics. Most importantly, potential direct clinical benefits of this research include early detection, improved and novel therapy, and better clinical outcomes for age-related diastolic dysfunction.