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.
