Role of the human gut microbiome in modulating age-associated aortic stiffening.

人类肠道微生物组在调节与年龄相关的主动脉硬化中的作用。

• 批准号: 10464510
• 负责人: Nathan Thomas Greenberg
• 金额: $ 3.93万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-12 至 2025-08-11
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464510
• 关键词: Address; Adult; Advanced Glycosylation End Products; Age; Aging; Aorta; Aortitis; Arteries; Bacteria; Biochemical; Biological Assay; Blood; Blood Circulation; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Carotid Arteries; Cell Wall; Cells; Clinical Trials; Colorado; Coupled; Data; Development; Disease; Dissection; Elderly; Exposure to; Fellowship; Flagellin; Funding; Future; Gram-Negative Bacteria; Human; Human Microbiome; Immune; Incubated; Inflammation; Inflammatory; International; Intestinal permeability; Laboratories; Lead; Learning; Lipopolysaccharides; Measurement; Measures; Mechanics; Mediating; Mentors; Modulus; Mononuclear; Mus; National Heart, Lung, and Blood Institute; Oxidative Stress; Pharmacology; Phenotype; Physiologic pulse; Physiology; Plasma; Prevention; Production; Reactive Oxygen Species; Recording of previous events; Research; Research Personnel; Research Priority; Research Project Grants; Research Training; Risk; Role; Scientist; Signal Transduction; Strategic vision; Structural Protein; Supervision; TLR4 gene; TNF gene; Techniques; Toll-like receptors; Training; Transplantation; United States National Institutes of Health; Universities; Work; age related; arterial stiffness; cardiovascular risk factor; clinical application; crosslink; cytokine; doctoral student; experience; fecal transplantation; graduate student; gut microbiome; gut microbiota; human microbiota; humanized mouse; in vivo; innovation; insight; microbiome composition; microbiota; mortality; mouse model; new therapeutic target; prevent; seal; skills; targeted agent; therapeutic target; vascular inflammation; young adult

PROJECT SUMMARY/ABSTRACT The purpose of this F31 application is to provide support for Mr. Nathan Greenberg, a 3rd year graduate student (1st year PhD student) in Dr. Douglas Seals’ (sponsor) laboratory at the University of Colorado Boulder, to conduct research and training that will prepare him to become an independent investigator in the field of translational cardiovascular (CV) aging research aimed at the prevention and treatment of age-related CV diseases (CVD). He plans to refine research skills currently under development and learn a variety of new technical, conceptual, and professional skills including working with human biospecimens, using pharmaco- dissection approaches in cultured aortic rings, conducting biochemical assays, and mastering measurement of in vivo aortic pulse wave velocity. Gut microbiome composition is uniquely altered with CVD and aging, and consequent gut-derived changes to the circulating milieu are related to CVD. However, whether these age- related changes causally increase aortic stiffness is unknown. Thus, the proposed research project seeks to establish the human gut microbiome as a key modulator of age-related aortic stiffening. Guided by strong preliminary data, Mr. Greenberg will determine, using innovative “humanized” mouse models: Aim 1: If age-related changes in the human gut microbiome directly increase aortic stiffness, accompanied by: i) increases in circulating lipopolysaccharide (LPS) and flagellin, 2 key components of bacterial cell walls that can enter circulation; ii) activation of toll-like receptors in circulating immune and/or vascular cells; iii) increased aortic inflammation and oxidative stress; iv) increased formation of advanced glycation end products; Aim 2: If aortic intrinsic mechanical stiffness is altered by the gut-derived “factors” in the circulating blood (“circulating milieu”) by exposing excised aorta rings to plasma from “humanized” mice; Aim 3: The mechanisms by which changes in the circulating milieu induced by the gut microbiome of older vs. young humans directly increases aortic stiffness using innovative “pharmaco-dissection” approaches. This research will be the first to investigate a causal role of the aging human gut microbiome and microbiome-derived circulating milieu in mediating arterial stiffening. If successful, this work will establish the human gut microbiome as a therapeutic target for treatment/prevention of age-related arterial stiffening. Overall, the proposed research has the potential to address two important NHLBI Strategic Vision research priorities: 1) investigate new pathobiological mechanisms important to the onset of CVD; and 2) identify novel therapeutic targets to prevent and treat CVD. Dr. Seals is an internationally recognized and NIH-funded scientist with a strong history of successful mentoring in translational CV research, particularly in “vascular aging”. Under his supervision and with the guidance of expert co-mentors Drs. Vienna Brunt, and Tiffany Weir, Mr. Greenberg will be able to successfully complete the proposed research and training plan, facilitating his ongoing development towards becoming an independent investigator in translational CV aging research.

项目摘要/摘要 此F31应用程序的目的是为三年级毕业生Nathan Greenberg先生提供支持 科罗拉多博尔德大学道格拉斯·海尔斯博士(赞助商)实验室的学生(一年级博士生)， 进行研究和培训，为他成为一名独立调查员做好准备 旨在预防和治疗年龄相关性心血管疾病的转化性心血管衰老研究 疾病(CVD)。他计划提炼目前正在开发的研究技能，并学习各种新的 技术、概念和专业技能，包括处理人类生物标本，使用药物- 培养的主动脉环的解剖方法，进行生化分析，并掌握测量 在体主动脉脉搏波速度。肠道微生物群的组成随着心血管疾病和衰老而独特地改变，并且 随之而来的肠源性循环环境改变与心血管疾病有关。然而，无论这些年龄- 相关改变导致的主动脉僵硬增加尚不清楚。因此，拟议的研究项目力求 建立人体肠道微生物群作为与年龄相关的主动脉僵硬的关键调节因子。以Strong为指导 根据初步数据，格林伯格将使用创新的“人性化”老鼠模型来确定： 目的1：如果与年龄相关的人体肠道微生物群的变化直接增加了主动脉僵硬，则伴随 通过：i)增加细菌细胞壁的两个关键成分--循环中的脂多糖和鞭毛蛋白 可进入循环的；ii)循环免疫和/或血管细胞中Toll样受体的激活；iii) 增加了主动脉炎症和氧化应激；iv)晚期糖基化终末产物的形成增加； 目的2：循环血液中的肠源性“因子”是否改变了主动脉固有的机械硬度 (“循环环境”)，通过将切除的主动脉环暴露于来自“人源化”小鼠的血浆； 目的3：老年人肠道微生物群引起循环环境改变的机制 与年轻人相比，使用创新的“药物分离”方法直接增加了主动脉僵硬。 这项研究将首次调查人体肠道微生物群老化的原因和作用 微生物组衍生的循环环境在调节动脉硬化中的作用。如果成功，这项工作将建立 人体肠道微生物群作为治疗/预防老年性动脉硬化的治疗靶点。 总体而言，拟议的研究有可能解决两个重要的NHLBI战略愿景研究 优先事项：1)研究对心血管疾病发病具有重要意义的新的病理生物学机制；2)确定新的 预防和治疗心血管疾病的治疗靶点。Seals博士是国际公认的NIH资助的 在翻译简历研究方面有丰富的成功指导历史的科学家，特别是在血管研究方面 老龄化“。在他的监督和专家共同导师维也纳·布伦特博士和蒂凡尼·韦尔的指导下， 格林伯格先生将能够成功完成拟议的研究和培训计划，促进他的 正在朝着成为翻译简历老化研究的独立调查者的方向发展。