Role of the human gut microbiome and related metabolites for causally mediating vascular endothelial function

项目总结/摘要 这个F31应用程序的目的是为阿比盖尔·卡索女士，在博士二年级博士生提供支持。 科罗拉多博尔德大学的道格拉斯海豹实验室，进行研究和培训 这将使她成为翻译心血管（CV）领域的独立研究者 衰老研究，旨在预防和治疗与年龄相关的心血管疾病（CVD）。公主随 她建议的培训计划，她的目标是完善目前正在发展的研究技能，并学习各种 新的技术，概念和专业技能，包括临床前小鼠模型的使用和获得 使用人类生物标本、细胞培养生物测定和代谢组学方法的新经验。她 一项拟议的研究项目旨在调查与年龄相关的变化在人类肠道微生物组中的作用 和循环肠道微生物组衍生的代谢物在损害血管内皮功能中的作用。肠道微生物组 组成是独特的改变与心血管疾病和老化，以及年龄相关的变化，循环浓度的 某些肠源性代谢物与CVD有关。然而，这些与年龄有关的变化是否 内皮功能受损的原因尚不清楚。在强有力的初步数据的指导下，卡索女士将确定： (Aim 1）如果人类肠道微生物组中与年龄相关的变化由于增加的细胞内毒素而损害内皮功能， 氧化应激和减少一氧化氮生物利用度使用创新的“人源化”小鼠模型和实验 体内“药物解剖”技术;（目的2A）年龄相关的肠道微生物组诱导的变化对 使用细胞培养生物测定法测定血浆循环因子对内皮功能的影响;（目的2B） 通过靶向代谢组学，衰老的人类肠道微生物组改变代谢物;以及（目的3）如果特异性 肠源性代谢物在循环中随年龄增加直接诱导内皮功能障碍， 细胞培养和分离的血管方法。预期的结果将确定新的肠道微生物组相关的 和循环肠衍生代谢物调节内皮功能，并可能促进这些翻译 代谢物作为预防和治疗年龄相关内皮功能障碍的新治疗靶点。 总体而言，拟议的研究有可能解决重要的NHLBI战略愿景研究 优先事项，包括：1）研究新的病理生物学机制的重要性，以心血管疾病的发病;和2） 鉴定新的治疗靶点以预防和治疗CVD 113。Seals博士是国际公认的， NIH资助的科学家，在翻译CV研究方面具有成功指导的悠久历史，特别是在 新兴的“血管老化”领域。在他的监督和内容专家的指导下， 导师博士维也纳布伦特，安吉洛D 'Alessandro，和蒂芙尼威尔，卡索女士将能够成功地 完成拟议的研究和培训计划，促进她不断发展，成为一个 机械和转化CV老化研究的独立调查员。

PROJECT SUMMARY/ABSTRACT The purpose of this F31 application is to provide support for Ms. Abigail Casso, a 2nd year PhD student in Dr. Douglas Seals’ (sponsor) laboratory at the University of Colorado Boulder, to conduct research and training that will prepare her 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). As part of her proposed training plan, she aims to both refine research skills presently under development and learn a variety of new technical, conceptual, and professional skills, including the use of preclinical mouse models and gaining new experiences using human biospecimens, cell culture bioassays, and metabolomics approaches. Her proposed research project seeks to investigate the role of age-related changes in the human gut microbiome and circulating gut microbiome-derived metabolites in impairing vascular endothelial function. Gut microbiome composition is uniquely altered with CVD and aging, and age-related changes in circulating concentrations of certain gut-derived metabolites have been related to CVD. However, whether these age-related changes causally impair endothelial function is unknown. Guided by strong preliminary data, Ms. Casso will determine: (Aim 1) If age-related changes in the human gut microbiome impair endothelial function due to increased oxidative stress and reduced nitric oxide bioavailability using innovative “humanized” mouse models and ex vivo “pharmaco-dissection” techniques; (Aim 2A) The effect of age-related, gut microbiome-induced changes in plasma circulating factors on endothelial function using cell culture bioassays; (Aim 2B) Which circulating metabolites are altered by the aging human gut microbiome via targeted metabolomics; and (Aim 3) If specific gut-derived metabolites that are increased in circulation with age directly induce endothelial dysfunction using cell culture and isolated vessel approaches. The expected results will identify novel gut microbiome-related and circulating gut-derived metabolite modulators of endothelial function and may facilitate translation of these metabolites as new therapeutic targets for prevention and treatment of age-related endothelial dysfunction. Overall, the proposed research has the potential to address important NHLBI Strategic Vision research priorities, including: 1) investigate new pathobiological mechanisms important to the onset of CVD; and 2) identify novel therapeutic targets to prevent and treat CVD113. Dr. Seals is an internationally recognized and NIH-funded scientist with a strong history of successful mentoring in translational CV research, particularly in the emerging field of “vascular aging”. Under his supervision and with the guidance of content expert co- mentors Drs. Vienna Brunt, Angelo D’Alessandro, and Tiffany Weir, Ms. Casso will be able to successfully complete the proposed research and training plan, facilitating her ongoing development towards becoming an independent investigator in mechanistic and translational CV aging research.