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.

项目概要/摘要 本次K99/R00申请的目的是为Vienna Brunt博士提供支持，他是一位有前途的博士后 道格拉斯·西尔斯博士实验室的研究员，进行额外的研究和培训，使她能够 成功转型为转化心血管衰老领域的独立研究者 预防心血管疾病（CVD）。作为她提出的 K99 培训计划的一部分，她将学习新的知识 技术技能，提高她的智力和专业技能，获得宝贵的指导并参与 各种职业发展活动，包括那些有助于使她成为肠道领域领导者的活动 微生物组相关的心血管研究。她提出的研究项目旨在调查以下因素的影响 口服补充短链脂肪酸乙酸酯可改善与年龄相关的动脉功能障碍 （即 CVD 的主要危险因素），首先在小鼠中（K99 期），然后在人类中（R00 期）。短链 脂肪酸是肠道微生物依赖的膳食可溶性纤维发酵的副产品，被认为 调节高纤维饮食的许多健康益处。在强有力的初步数据的指导下，布伦特博士将首先 （目标 1）证实补充醋酸盐对改善老年小鼠动脉功能的功效。有指导 并接受机械心血管研究领域领先专家的技术技能培训，然后她将（目标 2) 在小鼠离体动脉和培养的内皮细胞中进行创新的 siRNA 实验 确定乙酸盐介导的动脉功能改善机制，特别是游离乙酸盐的作用 脂肪酸受体 (FFAR)3 和心脏病转录因子早期生长的下调 响应-1 (Egr-1)。过渡到教职职位后，布伦特博士接下来（目标 3；R00 阶段）将翻译她 通过进行随机、安慰剂对照、双盲、平行设计的临床试验对人类进行的研究结果 在中年晚期到老年人（³50 岁）中调查 12 周口服补充剂的效果 醋酸盐对动脉功能的影响。她还将使用尖端的体内和离体方法来阐明 底层机制。总体而言，拟议的研究有可能解决两个重要的战略问题 NHLBI 的研究重点：1）研究对 CVD 发生重要的新病理生物学机制， 2）确定一种新的治疗策略来预防和治疗与年龄相关的动脉功能障碍，从而 降低心血管疾病的风险。拟议的研究将为未来的资助提供大量想法和机会 研究，最终在该奖项的第 4-5 年期间提交了一部新颖的 R01。主要导师，博士。 Seals 是一位国际公认的、由美国国立卫生研究院 (NIH) 资助的科学家，在以下领域拥有成功指导的悠久历史： 转化心血管研究。在他和联合导师 Leslie Leinwand 博士的指导下， 顾问团队成员 Drs. Mike Widlansky、Rob Knight 博士和 Michel Chonchol 以及生物统计学家 Dr. 尤志英博士布伦特将能够成功完成拟议的研究和培训计划 过渡到顶级 (R1) 研究机构的独立、外部资助的终身教授职位。