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 该F31申请的目的是为Nathan Greenberg先生提供支持，这是三年级的毕业生 科罗拉多大学博尔德大学的道格拉斯·海·塞尔斯（Douglas Seals）（赞助商）实验室的学生（第一年博士生） 进行研究和培训，以使他成为一个领域的独立调查员 转化心血管（CV）衰老研究旨在预防与年龄相关的CV 疾病（CVD）。新的新新新新的新新。 使用Pharmaco- 培养的主动脉环，进行生化测定和掌握测量的解剖方法 体内主动脉脉冲波速度。 随之而来的肠道衍生的变化与CVD有关。 相关变化的Causaly增加了主动脉僵硬，因此拟议的研究项目试图 建立人类肠道微生物组作为与年龄相关的主动脉僵硬的关键模块 初步数据，格林伯格先生将使用创新的“人性化”小鼠模型来确定： AIM 1：如果与年龄相关的人类肠道微生物组的变化直接增加刚度，则伴随 作者：i）增加循环脂多糖（LPS）和鞭毛蛋白，这是细菌细胞壁的两个关键成分 可以进入循环； 主动脉炎症和氧化应激增加 AIM 2：如果肠道上的肠道“因子”改变了主动脉固有的机械刚度刚度 （“循环环境”）通过将切除的主动脉环暴露于“人性化”小鼠的血浆中； AIM 3：老年肠道微生物组引起的循环环境变化的机制 与年轻人直接使用创新的“药物滴定”方法直接增加主动脉僵硬。 这项研究将是第一个研究人类肠道微生物组和 微生物组衍生的循环环境在内侧僵硬。 人类肠道微生物组是治疗/预防年龄相关替代僵硬的治疗靶标。 总体而言，支撑研究有可能解决两项重要的NHLBI战略愿景研究 优先级：1）研究对CVD发作至关重要的新病理学机制； 预防和治疗CVD的治疗靶标。 科学家在转化简历研究中有着悠久的成功指导的历史，部分 在他的监督下，在维也纳博士和蒂法尼·威尔（Tiffany Weir）的指导下， 格林伯格先生将能够成功完成支撑研究和培训计划，从而促进他的 持续发展成为转化简历衰老研究中的独立研究者。