Therapeutic activation of AMPK for the aging right heart

项目总结/摘要 本应用程序的首要目标是了解右心室（RV）功能的性别差异以及如何 这些差异在整个生命过程中会发生变化。Dr. Bruns目前是K01获奖者（K01 AG058819）， 在心脏衰老方面的专业知识不断增长，对性别差异如何导致心脏衰老产生浓厚兴趣。在 年龄相关性左心衰以及其他临床背景下，右心室（RV）功能障碍是 死亡率的最强预测因子。然而，尽管右心功能与生存率之间存在明确的联系， 关于RV功能随年龄的变化知之甚少，并且不存在针对RV的治疗。通过正在进行的工作， 在亲本K01中，我们已经确定了RV发病机制和RV对 治疗干预。然而，家长奖是动力不足，机械地理解， 男性和女性RV功能的差异以及它如何随着年龄的增长而变化。因此，这一目的 补充是使用诊断相关的临床前 RV中心疾病模型。我们将评估年龄和性别差异的肌张力介导机制 在RV功能-一个主要的重点培训和科学培训的父母奖。因此 我们建议的实验完全在母体奖的范围内。我们将通过增加 样本量，以增加统计分析性别差异的能力。由此取得的成果 补充将推进ORWH的战略目标，促进严格的研究，改善基础 了解性别如何影响RV老化和RV疾病。

PROJECT SUMMARY/ABSTRACT The overarching goal of this application is to understand sex differences right ventricular (RV) function and how these differences change across the life-course. Dr. Bruns is a current K01 awardee (K01 AG058819) with growing expertise in cardiac aging and a strong interest in how sex differences contribute to cardiac aging. 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 and no RV-directed therapies exist. Through ongoing work as part of the parent K01, we have identified preliminary sex differences in RV pathogenesis and in the RV response to therapeutic interventions. However, the parent award is underpowered to mechanistically understand the differences in male and female RV function and how it changes with advanced age. Therefore, the aim of this supplement is to mechanistically investigate RV sex differences using a translationally relevant pre-clinical model of RV-centric disease. We will assess myofilament-mediated mechanisms of age- and sex differences in RV function- a primary focus of the training and scientific training of the parent award. Therefore, the experiments we propose are well within the scope of the parent award. We will achieve this goal by increasing sample sizes to increase power to statistically analyze sex differences. The outcomes achieved by this supplement will advance the ORWH strategic goal of promoting rigorous research that improves fundamental understanding of how sex influences the aging RV and RV disease.