Androgens and Myocardial Relaxation in the Aging Heart

描述（由申请人提供）：本提案旨在支持Theodore Abraham医学博士，梅奥医学院内科助理教授的职业发展。申请人的职业目标是在一个充满活力和刺激的科学环境中，开发一个独立的，动态的，转化的研究项目，整合创新的成像模式和肌肉生理学。KO8奖励将保护申请人免于临床职责，如超声心动图实验室的人员配置，并允许全职研究。申请人计划加强正在进行的临床研究，提高他在肌肉生理学，内分泌学和衰老方面的专业知识和独立性，在资深，成熟的研究人员的指导下。这项建议的科学目标是检查睾酮在与年龄相关的舒张功能障碍发展中的作用。衰老与舒张功能障碍有关，舒张功能障碍在老年人中导致显著的发病率和死亡率。由于睾酮水平随着年龄的增长而下降，因此假设睾酮缺乏是舒张功能障碍发生的病理生理基础，而睾酮替代可以缓解老年人的舒张功能障碍。利用创新的成像技术，申请人最近介绍了与年龄相关的舒张功能障碍明显相关的新概念。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（申请人是心血管部分的项目负责人）的背景下，测试睾酮缺乏是否会恶化，替代是否会减轻老年人的舒张功能障碍；B)在相同的环境下，检查睾酮是否通过调节外周血流动力学介导舒张功能；c)在动物模型中，探索睾酮介导的舒张功能障碍的潜在细胞机制，特别是细胞内钙调节。提出的实验将产生与年龄相关的舒张功能障碍有关的重要新知识，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，该研究的潜在直接临床益处包括早期发现，改进和新颖的治疗方法，以及更好的与年龄相关的舒张功能障碍的临床结果。

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.