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

摘要 老年人身体机能的下降和残疾的出现对 健康和长寿是受影响个人的健康和长寿，也是医疗成本上升的主要原因。治疗性的 目前，保存身体机能的策略有限。初步证据表明， 肾素-血管紧张素系统(RAS)是新的治疗方法开发的一个有前途的靶点 功能衰退。然而，目前还缺乏关于最近一次- 发现RAS的血管扩张臂，主要受生物活性物质的作用调节 血管紧张素转换酶2(ACE2)将血管紧张素I和血管紧张素II转化为血管紧张素-(1-7)。这个项目将 通过评估直接给老年大鼠血管紧张素转换酶2的影响来解决这一知识缺口 保留身体机能。我们假设ACE2轴的直接药物激活将 延缓晚年的功能衰退。我们将以三个具体目标来解决这一假设，这三个目标是： 1)证明系统地服用ACE2改善了老年Fischer 344 x的身体功能 棕色挪威(F344/BN)大鼠，2)证明ACE2改善了对体育锻炼的功能反应， 以及3)确定与给予ACE2的功能反应相关的生理适应 与世隔绝，并结合锻炼。预期影响：我们设计了这项研究，使其具有 有可能被迅速转化为人类。这项研究将填补知识上的一个重要空白，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。这项研究 意义重大，因为它解决了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反向翻译 我们之前在这方面的工作，针对RAS的健康益处，而不是调节血压， 以及在提供治疗化合物和使用基质辅助的方法方面的创新 激光解吸电离(MALDI)质谱仪评估组织水平对 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.