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: 9323124
• 负责人: Thomas W Buford
• 金额: $ 30.44万
• 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/9323124
• 关键词: Address; Adverse reactions; Affect; Age; Age-Months; Aging; American; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Area; Attenuated; Biological Preservation; 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; 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; improved; innovation; male; mortality; novel; novel therapeutics; physical conditioning; pre-clinical; 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.

摘要