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

项目摘要/摘要 此K99/R00应用程序的目的是为维也纳·布伦特博士提供支持，他是一位有前途的博士后 Douglas Seals博士实验室的研究员，进行额外的研究和培训，使她能够 成功转型为转化性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，获得宝贵的指导和参与 各种职业发展活动，包括那些将帮助她成为胆识领域领导者的活动 与微生物群相关的心血管研究。她提出的研究项目旨在调查 口服短链脂肪酸醋酸酯改善老年性动脉功能障碍 (即，心血管疾病的主要危险因素)，首先在小鼠(K99期)，然后在人类(R00期)。短链 脂肪酸是肠道微生物群依赖的膳食可溶性纤维发酵的副产品，被认为是 调节了高纤维饮食对健康的许多好处。在强劲的初步数据的指导下，布伦特博士将首先 (目的1)证实补充醋酸盐对老年小鼠动脉功能的改善作用。有指导的 和机械心血管研究领域领先专家的技术技能培训，然后她将(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，以 确定醋酸盐介导的改善动脉功能的机制，特别是游离的作用 脂肪酸受体3与心脏病理转录因子早期生长的下调 响应-1(Egr-1)。在过渡到教员职位后，布伦特博士将接下来(Aim 3；R00阶段)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 在50岁以上的中老年人群中研究12周口服补充剂的效果 醋酸盐对动脉功能的影响。她还将使用体内和体外的尖端方法来阐明 潜在的机制。总体而言，拟议的研究有可能解决2个重要的战略问题 NHLBI的研究重点：1)研究与CVD发病有关的新的病理生物学机制， 以及2)确定预防和治疗年龄相关性动脉功能障碍的新治疗策略，从而 降低心血管疾病的风险。拟议的研究将为未来的可资助项目提供大量的想法和机会 研究，最终在该奖项的第4-5年期间提交小说R01。这位主要的导师，Dr。 Seals是一位国际公认的NIH资助的科学家，在 转化性心血管研究。在他的指导和共同导师Leslie Leinwand博士的指导下， 咨询团队成员Mike Widlansky博士、Rob Knight博士和Michel Chonchol博士以及生物统计学家Dr。 有了智盈，布伦特博士将能够顺利完成拟议的研究和培训计划，并 过渡到一家顶级研究机构(R1)的独立、外部资助的终身教职轨道职位。

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.