Androgens and Myocardial Relaxation in the Aging Heart

描述(由申请人提供)：本提案旨在支持梅奥医学院内科助理教授西奥多·亚伯拉罕医学博士的职业发展。申请者的职业目标是开发一个独立的、动态的、转化性的研究项目，在一个充满活力和激励的科学环境中，整合创新的成像方式和肌肉生理学。KO8奖将保护申请者免除临床职责，如为超声心动图实验室配备人员，并允许进行全职研究。申请者计划加强正在进行的临床研究，并在资深、成熟的研究人员的指导下，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。这项建议的科学目标是研究睾酮在年龄相关性舒张期功能障碍发展中的作用。衰老与舒张性功能障碍有关，这会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降低，因此假设睾酮缺乏形成了舒张期功能障碍的病理生理学基础，而睾酮替代疗法可以缓解老年患者的舒张期功能障碍。使用创新的成像技术，申请人最近提出了新的概念，在年龄相关的舒张期功能障碍中具有明显的含义。这项建议试图扩大这些观察结果，并计划：a)在NIH资助的一项随机、双盲、安慰剂对照的临床研究中(申请人是心血管部分的项目负责人)，测试睾酮缺乏是否会加剧老年人的舒张期功能障碍，而替代治疗是否会缓解老年人的舒张期功能障碍；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来调节舒张期功能；以及c)在动物模型中，探索睾酮介导的舒张期功能障碍的可能细胞机制，尤其是细胞内钙调节。拟议的实验将产生与年龄相关的舒张期功能障碍相关的重要新知识，特别是关于荷尔蒙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、改进和新的治疗方法，以及更好的老年相关舒张期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.