Translational Studies of the Short-Chain Fatty Acid Acetate for Improving Age-Associated Arterial Dysfunction

短链脂肪酸乙酸酯改善年龄相关动脉功能障碍的转化研究

• 批准号: 10326858
• 负责人: Vienna E Brunt
• 金额: $ 17.43万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-07 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326858
• 关键词: Acetates; Acute; Address; Adult; Advanced Glycosylation End Products; Advisory Committees; Age; Age-Years; Aging; American; Arteries; Ascorbic Acid; Award; Biological Availability; Biopsy; Blood Circulation; C57BL/6 Mouse; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cause of Death; Clinical; Clinical Trials; Clinical Trials Design; Collagen; Data; Diet; Dietary Fiber; Digestion; Double-Blind Method; Down-Regulation; Effectiveness; Elastin; Elderly; Endothelial Cells; Endothelium; Extramural Activities; FFAR3 gene; Faculty; Female; Fermentation; Fiber; Functional disorder; Funding; Future; Genes; Genetic Transcription; Goals; Growth; Health; Health Benefit; Human; Impairment; Incubated; Infusion procedures; Institution; Intake; International; Intervention; Knock-out; Laboratories; Lead; Learning; Mediating; Mentors; Mentorship; Molecular; Morbidity - disease rate; Mus; NG-Nitroarginine Methyl Ester; National Heart, Lung, and Blood Institute; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Nonesterified Fatty Acids; Oral; Oxidative Stress; Pathology; Phase; Physiologic pulse; Physiological; Placebo Control; Placebos; Plasma; Population; Positioning Attribute; Postdoctoral Fellow; Production; Proteins; Public Health; Randomized; Reactive Oxygen Species; Recording of previous events; Research; Research Personnel; Research Priority; Research Project Grants; Research Training; Role; Scientist; Serum; Small Interfering RNA; Structural Protein; Superoxide Dismutase; Superoxides; Supplementation; Surface; Technical Expertise; Training; Translating; United States National Institutes of Health; Vascular Endothelium; Volatile Fatty Acids; Woman; age related; arterial stiffness; brachial artery; cardiovascular disorder prevention; cardiovascular disorder risk; cardiovascular risk factor; career development; clinical development; dietary; drinking water; effective intervention; experimental study; gut microbiome; human subject; improved; in vivo; innovation; male; member; men; middle age; mimetics; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; oral supplementation; post intervention; pre-clinical; prevent; receptor; response; seal; skills; soluble fiber; tenure track; transcription factor; translational approach; translational study

PROJECT SUMMARY/ABSTRACT The purpose of this K99/R00 application is to provide support for Dr. Vienna Brunt, a promising postdoctoral fellow in the laboratory of Dr. Douglas Seals, to conduct additional research and training that will allow her to successfully transition into an independent investigator in the field of translational cardiovascular aging and the prevention of cardiovascular diseases (CVD). As part of her proposed K99 training plan, she will learn new technical skills, enhance her intellectual and professional skills, gain valuable mentorship and participate in various career development activities, including those that will help establish her as a leader in the field of gut microbiome-related cardiovascular research. Her proposed research project seeks to investigate the effects of oral supplementation with the short-chain fatty acid acetate on improving age-related arterial dysfunction (i.e., the primary risk factor for CVD), first in mice (K99 phase) and later in humans (R00 phase). Short-chain fatty acids are byproducts of gut microbiome-dependent fermentation of dietary soluble fiber and are thought to mediate many of the health benefits of high-fiber diets. Guided by strong preliminary data, Dr. Brunt will first (Aim 1) confirm efficacy of acetate supplementation for improving arterial function in old mice. With guidance and training in technical skills from leading experts in mechanistic cardiovascular research, she will then (Aim 2) conduct innovative siRNA experiments in both mouse isolated arteries and cultured endothelial cells to determine the mechanisms of acetate-mediated improvements in arterial function, specifically the roles of free fatty acid receptor (FFAR)3 and downregulation of the cardiopathological transcription factor early growth response-1 (Egr-1). After transitioning to a faculty position, Dr. Brunt will next (Aim 3; R00 phase) translate her findings to humans by conducting a randomized, placebo-controlled, double-blind, parallel-design clinical trial in late middle-aged to older (³50 years) adults investigating the effects of 12 weeks of oral supplementation with acetate on arterial function. She will also use cutting-edge in vivo and ex vivo approaches to elucidate the underlying mechanisms. Overall, the proposed research has the potential to address 2 important strategic research priorities of NHLBI: 1) investigate new pathobiological mechanisms important to the onset of CVD, and 2) identify a novel therapeutic strategy to prevent and treat age-associated arterial dysfunction, thereby reducing risk of CVD. The proposed research will provide numerous ideas and opportunities for future fundable research, culminating in submission of a novel R01 during years 4-5 of this award. The primary mentor, Dr. Seals, is an internationally-recognized and NIH funded scientist with a strong history of successful mentoring in translational cardiovascular research. With his guidance and the guidance of co-mentor Dr. Leslie Leinwand, advisory team members Drs. Mike Widlansky, Dr. Rob Knight, and Michel Chonchol, and biostatistician Dr. Zhiying You, Dr. Brunt will be able to successfully complete the proposed research and training plan and transition to an independent, extramurally-funded tenure-track position at a top-tier (R1) research institution.

项目总结/文摘