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

项目总结/摘要 这个K99/R 00应用程序的目的是为博士提供支持。维也纳布伦特，一个有前途的博士后 研究员在实验室的博士道格拉斯海豹，进行额外的研究和培训，使她能够 成功过渡到一个独立的研究者在翻译心血管衰老和 预防心血管疾病（CVD）。作为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，并参与 各种职业发展活动，包括那些将有助于建立她作为肠道领域的领导者 微生物组相关的心血管研究。她提出的研究项目旨在调查 口服补充短链脂肪酸乙酸酯改善年龄相关的动脉功能障碍 (i.e., CVD的主要危险因素），首先在小鼠中（K99期），随后在人类中（R 00期）。短链 脂肪酸是可溶性膳食纤维的肠道微生物群依赖性发酵的副产物， 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 (Aim 1）证实乙酸盐补充对于改善老年小鼠的动脉功能的功效。重要思想为指导 并接受心血管机械研究领域领先专家的技术技能培训，然后她将（Aim 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， 确定醋酸盐介导的动脉功能改善的机制，特别是游离 脂肪酸受体（FFAR）3和心脏病理转录因子早期生长的下调 响应-1（Egr-1）。在过渡到教师职位后，Brunt博士将在下一个（目标3; R 00阶段）为她翻译 通过进行一项随机、安慰剂对照、双盲、平行设计的临床试验， 在中年晚期至老年人（≥ 50岁）中，研究12周口服补充剂的效果 对动脉功能的影响她还将使用尖端的体内和体外方法来阐明 基本机制。总体而言，拟议的研究有可能解决2个重要的战略问题 NHLBI的研究重点：1）研究对CVD发病重要的新的病理生物学机制， 和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CVD的风险。拟议的研究将为未来的可资助项目提供许多想法和机会。 研究，最终在该奖项的第4-5年提交了一部小说R 01。主要的导师，博士。 Seals是一位国际公认的和NIH资助的科学家，在以下方面有着成功的指导历史： 转化性心血管研究在他的指导和共同导师莱斯利·莱因万德博士的指导下， 顾问团队成员Mike Widlansky博士、Rob Knight博士和Michel Chonchol博士以及生物统计学家Dr. Brunt博士将能够成功完成拟议的研究和培训计划， 过渡到一个独立的，校外资助的终身职位在顶级（R1）研究机构。

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.