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

ACE2 作为一种新型疗法，可保护晚年身体功能

• 批准号: 9813211
• 负责人: Thomas W Buford
• 金额: $ 6.35万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813211
• 关键词: Address; Adverse reactions; Affect; Age; Age-Months; Aging; American; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Area; Attenuated; Biological; Climacteric; Clinical; Clinical Research; Clinical Trials; Collaborations; Data; Development; Dose; Drug Delivery Systems; Elderly; Evidence Based Medicine; Exercise; Fatty acid glycerol esters; Female; Fiber; Fibrosis; Frequencies; Future; Goals; Health; Health Benefit; Health Care Costs; Homologous Gene; Hospitalization; Human; Individual; Infiltration; Inflammation; Intervention; Knowledge; Literature; Longevity; Maintenance; Measures; Metabolism; Methodology; Methods; Mission; Morbidity - disease rate; Operative Surgical Procedures; Oral; Oral Administration; Peptides; Peptidyl-Dipeptidase A; Personal Satisfaction; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Physical Exercise; Physical Function; Physically Handicapped; Physiological Adaptation; Placebos; Plants; Population; Prevention; Public Health; Publishing; Randomized; Rattus; Rattus norvegicus; Recombinant Proteins; Recording of previous events; Recovery; Renin-Angiotensin System; Research; Research Design; Resources; Risk; Rodent Model; Role; Scientist; Signal Transduction; Skeletal Muscle; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Testing; Therapeutic; Time; Tissues; Translating; Translational Research; Translations; United States National Institutes of Health; Work; angiotensin I (1-7); arm; base; blood pressure regulation; cost; design; disability; efficacy study; functional decline; glucose metabolism; healthy aging; human model; improved; innovation; male; mortality; novel; novel therapeutics; physical conditioning; pre-clinical; preservation; prevent; public health relevance; response; therapy development; treadmill; treatment group

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.

抽象的 老年人身体机能下降和残疾的发生对老年人的生活产生巨大影响。 影响个人的健康和寿命，并且是医疗费用上涨的主要原因。治疗性 目前保护身体功能的策略有限。初步证据表明 肾素-血管紧张素系统（RAS）是开发预防新疗法的有希望的目标 功能衰退。然而，目前对最近的直接影响缺乏了解—— 发现 RAS 的血管舒张臂主要受生物活性剂的作用调节 血管紧张素转换酶 2 (ACE2) 将血管紧张素 I 和 II 转化为血管紧张素-(1-7)。该项目将 通过评估直接给予老年大鼠 ACE2 的影响来解决这一知识差距 保持身体机能。我们假设 ACE2 轴的直接药理学激活将 减轻晚年的功能衰退。我们将通过三个具体目标来解决这一假设，即： 1) 证明 ACE2 的全身给药可改善老年 Fischer 344 x 的身体功能 棕色挪威 (F344/BN) 大鼠，2) 证明 ACE2 改善对体育锻炼的功能反应， 3) 确定与 ACE2 给药的功能反应相关的生理适应 隔离并与运动相结合。预期影响：我们设计了这项研究，以便它能够 具有快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 为后续设计人类研究以检验我们的中心假设提供重要数据。研究 其意义重大，因为它解决了 NIH 认为重要的几个临床和公共卫生问题： 以及科学文献中的一个重要空白。该项目的创新包括反向翻译 我们之前在这一领域的工作，除了调节血压之外，还针对 RAS 带来的健康益处， 治疗化合物的递送和基质辅助的使用方面的方法创新 激光解吸电离 (MALDI) 质谱法评估组织水平对 干预措施。