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: 10580872
• 负责人: Vienna E Brunt
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580872
• 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.

项目摘要/摘要 该K99/R00申请的目的是为维也纳博士Brunt提供支持，这是一个有希望的博士后 Douglas Seals博士实验室的研究员进行了其他研究和培训，这将使她能够 成功地过渡到转化心血管衰老领域的独立研究者和 预防心血管疾病（CVD）。作为她建议的K99培训计划的一部分，她将学习新的 技术技能，提高她的智力和专业技能，获得价值心态并参与 各种职业发展活动，包括那些将帮助她成为肠道领域的领导者的活动 与微生物组相关的心血管研究。她提出的研究项目旨在调查 用短链脂肪酸乙酸盐的口服补充，以改善与年龄相关的人伪像 （即CVD的主要危险因素），首先是小鼠（K99期），后来在人类（R00期）。短链 脂肪酸是饮食固体纤维的肠道微生物组依赖性发酵的副产物，被认为是 调解高纤维饮食的许多健康益处。在强大的初步数据的指导下，Brunt博士将首先 （AIM 1）确认补充乙酸以改善旧小鼠的动脉功能的效率。有指导 她将在机械性心血管研究领域领先专家的技术技能方面培训（AIM） 2）在小鼠分离的动脉和培养的内皮细胞中进行创新的siRNA实验至 确定乙酸盐介导的动脉功能改善的机制，特别是游离的作用 脂肪酸受体（FFAR）3和心理转录因子早期生长的下调 响应1（EGR-1）。过渡到教师职位后，Brunt博士接下来（AIM 3; R00阶段）将她翻译 通过进行随机，安慰剂对照，双盲，平行设计临床试验来向人类的发现 在中年晚期到年龄较大（六50年）的成年人，研究了12周的口服补充作用 乙酸具有动脉功能。她还将使用尖端的体内和离体方法来阐明 基本机制。总体而言，拟议的研究有可能解决2个重要策略 NHLBI的研究优先级：1）研究对CVD发作至关重要的新病理生物学机制， 2）确定一种新型的热策略来预防和治疗与年龄相关的动脉功能障碍，从而 降低CVD的风险。拟议的研究将为未来的基本提供许多想法和机会 研究，最终在本奖项的4 - 5年内提交新颖的R01。主要导师，博士 海豹是一位国际公认和NIH资助的科学家，具有成功的心理历史 转化心血管研究。在他的指导和同事Leslie Leinwand博士的指导下 咨询团队成员Drs。 Mike Widlansky，Rob Knight博士和Michel Chonchol和Biostaticational博士 Zhiyy You，Brunt博士将能够成功完成拟议的研究和培训计划， 在顶级研究机构（R1）研究机构过渡到独立的，外部资助的终身制位置。