Therapeutic activation of AMPK for the aging right heart

点击翻译按钮获取中文摘要

ABSTRACT/PROJECT SUMMARY The overarching goal of this application is to provide Dr. Bruns the scientific and career development for a successful independent research career in the field of cardiac aging, with a specific focus on the right ventricle. Heart failure (HF) is a major public health concern within aging populations. In age-related left-sided heart failure as well as other clinical contexts, right ventricular (RV) dysfunction is the strongest predictor of mortality. However, despite the clear link between right heart function and survival, very little is known about RV function with age. This knowledge gap underscores the need to assess the impact of aging on the RV with the long-term goal of developing therapeutics that target declining RV function. Although no RV- directed therapies exist, epidemiological data and preliminary data from our lab suggest that activation of AMP-activated protein kinase (AMPK) may be beneficial through novel and direct action on the cardiac contractile apparatus. Accordingly, the global hypothesis of this project is that aging exacerbates RV dysfunction, and contractile apparatus-mediated mechanisms can be exploited for novel therapies for the aging right heart. To address this hypothesis, we propose two specific aims: 1) to assess the impact of age on two models of right heart failure- isolated RV pressure overload and hypobaric hypoxia (pulmonary hypertension)-induced RV dysfunction, a highly significant and translationally important disease in cardiovascular aging; and 2) to determine if activation of AMPK attenuates cardiac dysfunction in aged mice, and the mechanisms by which this occurs. We will investigate AMPK activation as a novel RV-directed therapy in cardiac aging using both genetic and pharmaceutical approaches, facilitating the elucidation of molecular mechanisms underlying cardiac dysfunction. The mentorship team and career development assembled to answer this translationally important question will provide training in aging biology, molecular genetics, and myofilament mechanics, important skills for a career as an independent cardiac aging scientist. Together, successful completion of this proposal will propel scientific independence by providing the training, mentorship, and scientific guidance upon which to build a successful research agenda in the field of cardiac aging biology.