Therapeutic activation of AMPK for the aging right heart

摘要/项目总结 该应用程序的首要目标是为博士提供.布伦斯的科学和职业生涯 在心脏衰老领域成功的独立研究事业的发展， 特别关注右心室心力衰竭（HF）是一个主要的公共卫生问题， 人口老龄化。在与年龄相关的左侧心力衰竭以及其他临床背景下，对 心室（RV）功能障碍是死亡率的最强预测因子。然而，尽管明确 右心功能与存活率之间的联系，对RV功能随年龄的变化知之甚少。 这一知识差距强调了评估老龄化对RV影响的必要性， 长期目标是开发针对RV功能下降的治疗方法。虽然没有RV- 定向治疗存在，流行病学数据和我们实验室的初步数据表明， AMP活化蛋白激酶（AMPK）的活化可能是有益的， 对心脏收缩器官的作用。因此，本项目的总体假设是 衰老加剧了RV功能障碍，收缩器官介导的机制可能是 用于治疗右心老化的新疗法。为了解决这个问题，我们建议 两个具体目标：1）评估年龄对两种右心衰竭模型的影响-孤立的 RV压力超负荷和低压缺氧（肺动脉高压）诱导的RV 功能障碍，心血管衰老中一种非常重要且具有重要意义的疾病; 和2）确定AMPK的激活是否减轻老年小鼠的心功能障碍，以及AMPK的激活是否减轻老年小鼠的心功能障碍。 这种情况发生的机制。我们将研究AMPK激活作为一种新的RV导向的 使用遗传和药物方法治疗心脏衰老， 阐明心功能不全的分子机制。导师团队和 职业发展聚集在一起，回答这个至关重要的问题，将提供 衰老生物学、分子遗传学和肌丝力学方面的培训， 作为一名独立的心脏衰老科学家。共同努力，圆满完成这一 该提案将通过提供培训、指导和科学研究， 指导在心脏衰老生物学领域建立一个成功的研究议程。

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.