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
基本信息
- 批准号:10580872
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcetatesAcuteAddressAdultAdvanced Glycosylation End ProductsAdvisory CommitteesAgeAge-YearsAgingAmericanArteriesAscorbic AcidAwardBiological AvailabilityBiopsyBlood CirculationC57BL/6 MouseCardiovascular DiseasesCardiovascular systemCarotid ArteriesCause of DeathClinicalClinical TrialsClinical Trials DesignCollagenDataDietDietary FiberDigestionDouble-Blind MethodDown-RegulationEffectivenessElastinElderlyEndothelial CellsEndotheliumExtramural ActivitiesFFAR3 geneFacultyFemaleFermentationFiberFunctional disorderFundingFutureGenesGenetic TranscriptionGoalsGrowthHealthHealth BenefitHumanImpairmentIncubatedInfusion proceduresInstitutionIntakeInternationalInterventionKnock-outLaboratoriesLeadLearningMediatingMentorsMentorshipMolecularMorbidity - disease rateMusNG-Nitroarginine Methyl EsterNational Heart, Lung, and Blood InstituteNitric OxideNitric Oxide Synthetase InhibitorNonesterified Fatty AcidsOralOxidative StressPathologyPhasePhysiologic pulsePhysiologicalPlacebo ControlPlacebosPlasmaPopulationPositioning AttributePostdoctoral FellowProductionProteinsPublic HealthRandomizedReactive Oxygen SpeciesRecording of previous eventsResearchResearch PersonnelResearch PriorityResearch Project GrantsResearch TrainingRoleScientistSerumSmall Interfering RNAStructural ProteinSuperoxide DismutaseSuperoxidesSupplementationSurfaceTechnical ExpertiseTrainingTranslatingUnited States National Institutes of HealthVascular EndotheliumVolatile Fatty AcidsWomanage relatedarterial stiffnessbrachial arterycardiovascular disorder preventioncardiovascular disorder riskcardiovascular risk factorcareer developmentclinical developmentdietarydrinking watereffective interventionexperimental studygut microbiomehuman subjectimprovedin vivoinnovationmalemembermenmiddle agemimeticsmortalitymouse modelnovelnovel therapeutic interventionnovel therapeuticsoral supplementationpost interventionpre-clinicalpreventreceptorresponsesealskillssoluble fibertenure tracktranscription factortranslational approachtranslational study
项目摘要
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/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。总的来说,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)确定预防和治疗年龄相关动脉功能障碍的新治疗策略,
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Vienna E Brunt其他文献
Vienna E Brunt的其他文献
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{{ truncateString('Vienna E Brunt', 18)}}的其他基金
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:
10634596 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
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