ACE2 as a novel therapeutic to preserve physical function in late life

摘要 老年人身体机能下降和出现残疾， 健康和长寿的影响，是一个核心因素，不断上升的医疗保健费用。治疗 目前，保护身体功能的策略是有限的。初步证据显示， 肾素-血管紧张素系统（RAS）是开发新的治疗药物以预防高血压的有希望的靶点。 功能衰退然而，目前缺乏关于最近一次- 发现了RAS的血管舒张臂，其主要由生物活性剂的作用调节 血管紧张素转化酶2（ACE 2）将血管紧张素I和II转化为血管紧张素-（1-7）。该项目将 通过评估直接给予ACE 2对老年大鼠的影响， 保持身体功能。我们假设ACE 2轴的直接药理学激活将 减缓晚年的功能衰退。我们将通过三个具体目标来解决这一假设，即： 1)证明ACE 2全身给药可改善老年人的身体功能Fischer 344 x Brown Norway（F344/BN）大鼠，2）证明ACE 2改善对体育锻炼的功能反应， 和3）鉴定与ACE 2给药的功能反应相关的生理适应， 与运动相结合。预期影响：我们设计了这项研究， 迅速转化为人类的潜力。这项研究将填补一个重要的知识空白，同时也 为随后的人体研究设计提供重要数据，以检验我们的中心假设。研究 重要的是，它解决了NIH认为重要的几个临床和公共卫生问题， 也是科学文献中的一个重要空白。该项目的创新之处包括： 我们之前在这一领域的工作，目标是RAS对健康的好处，而不是调节血压， 以及在递送治疗化合物和使用基质辅助的药物组合物方面的方法学创新。 激光解吸电离（MALDI）质谱，以评估组织水平的适应 干预措施。

ABSTRACT Declining physical function and the onset of disability among older persons has a tremendous impact on the health and longevity of affected individuals and is a central contributor to rising healthcare costs. Therapeutic strategies for the preservation of physical function are currently limited. Preliminary evidence suggests that the renin-angiotensin system (RAS) is a promising target for the development of new therapeutics to prevent functional decline. However there is currently a lack of knowledge regarding the direct impact of a recently- discovered vasodilatory arm of the RAS which is modulated primarily by the actions of the bioactive agent angiotensin converting enzyme 2 (ACE2) to convert angiotensin I and II to angiotensin-(1-7). This project will address this gap in knowledge by evaluating the impact of directly administering ACE2 to older rats in the preservation of physical function. We hypothesize that direct pharmacologic activation of the ACE2 axis will attenuate functional declines in late life. We will address this hypothesis with three specific aims, which are to: 1) Demonstrate that systemic administration of ACE2 improves physical function among older Fischer 344 x Brown Norway (F344/BN) rats, 2) Demonstrate that ACE2 improves functional responses to physical exercise, and 3) Identify physiologic adaptations associated with functional responses to ACE2 administration both in isolation and in combination with exercise. ANTICIPATED IMPACT: We have designed this study so that it has potential to be swiftly translated to humans. This study will fill an important gap in knowledge while also providing important data for the subsequent design of human studies to test our central hypothesis. The study is significant in that it addresses several clinical and public health problems deemed significant by the NIH as well as an important gap in the scientific literature. Innovations in the project include the reverse translation of our prior work in this area, targeting of the RAS for health benefits other than the regulation of blood pressure, and methodological innovations in the delivery of the therapeutic compound and the use of matrix-assisted laser desorption ionization (MALDI) mass spectrometry to evaluate tissue-level adaptations to the interventions.