Biological Mechanisms through which TMAO Promotes Atherosclerosis

TMAO促进动脉粥样硬化的生物学机制

基本信息

批准号：
10592245
负责人：
Hooman Allayee
金额：
$ 60.11万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-20 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592245
关键词：
Ablation Address Affect Animals Aorta Atherogenic Diet Atherosclerosis Biochemical Reaction Bioinformatics Biological Cardiac Cardiovascular Diseases Cause of Death Choline Clinical Complex Data Development Diet Dietary Factors Endothelial Cells Endothelium Enzymes Event Exhibits FMO3 Gene Expression Genes Genetic Genetic Determinism Genetic Engineering Genetic study Genomics Goals Hepatic Human Human Genetics Hybrids Hypertension In Vitro Inbred Strains Mice Inflammation Inflammatory Knockout Mice Knowledge Lesion Levocarnitine Lipids Liver Macrophage Maps Mediating Mendelian randomization Meta-Analysis Metabolism Mus Pathway interactions Patients Pharmaceutical Preparations Plasma Population Predisposition Process Production Property Renal function Risk Risk Factors Series Smooth Muscle Myocytes Source Synteny System United States atherogenesis body system cardiovascular disorder risk cardiovascular risk factor cell type cohort comparative dietary experimental study feeding genetic approach genome wide association study gut microbiome in silico in vivo insight instrument monocyte mouse model multi-ethnic new therapeutic target novel novel therapeutic intervention nutrition related genetics pharmacologic response single-cell RNA sequencing transcriptome sequencing trimethyloxamine

项目摘要

PROJECT SUMMARY Cardiovascular disease (CVD) remains the leading cause of death in the US but traditional risk factors, such as elevated lipid levels and hypertension, account for less than 50% of the risk for CVD. We have recently identified a novel mechanism for atherosclerosis where trimethylamine N-oxide (TMAO), a metabolite derived from gut microbiome and hepatic-mediated metabolism of dietary choline and L-carnitine, increases aortic lesion formation in mice and is associated with elevated risk of CVD in humans. Our data further indicate that TMAO levels are regulated through complex interactions between dietary substrates and host genetic factors in the liver and other organ systems. However, the biological pathways that regulate TMAO at the level of hepatic production and whether these factors interact with dietary choline or L-carnitine to affect atherosclerosis are not known. Furthermore, many questions remain unanswered with respect to the biological mechanisms by which TMAO promotes atherogenesis and whether the association between TMAO and CVD in humans represents a causal relationship. The integrative strategies proposed herein directly address these critical gaps in knowledge. In Specific Aim 1, we will determine the biological mechanisms underlying the pro- atherogenic properties of TMAO using a genetically modified mouse model that we recently created for deficiency of flavin-containing monooxygenase 3 (Fmo3), the major enzyme responsible for hepatic TMAO production. Fmo3 null mice will be comprehensively characterized for aortic lesion development in the context of a atherogenic high choline diet. We will also use pharmacological and genetic perturbations strategies in mouse models to determine in vivo whether the inflammatory processes TMAO promotes at the level of the vessel wall are mediated through the NF-B pathway. In Specific Aim 2, we will use comparative systems genetics strategies with >41,000 subjects and a panel of ~100 inbred mouse strains to identify genetic factors influencing plasma TMAO levels through main effects and/or gene-dietary interactions. The results of these synteny mapping studies will be used for in silico and Mendelian randomization analyses in >500,000 subjects to establish a causal relationship between TMAO and risk of CVD. In combination, the proposed studies have the potential to 1) elucidate the inflammatory mechanisms through which TMAO promotes atherosclerosis; 2) identify the genetic determinants of a novel and clinically important risk factor for CVD as well as provide a better understanding of how interactions between genes and dietary factors mediate changes in plasma TMAO levels and CVD risk; and 3) provide genetic evidence that the relationship between TMAO and CVD is causal. Taken together, results from our studies would support the notion that targeting TMAO is a novel therapeutic strategy that may decrease CVD risk independent of known biological pathways and risk factors.

项目摘要心血管疾病（CVD）仍然是美国死亡的主要原因，但传统的危险因素，例如脂质水平升高和高血压，占CVD风险的50％。我们有最近确定了一种新型动脉粥样硬化机制，其中三甲胺N-氧化物（TMAO），一种代谢物源自肠道胆碱和L-肉碱的肠道微生物组和肝介导的代谢，增加小鼠主动脉病变形成，与人类CVD风险升高有关。我们的数据进一步表明TMAO水平是通过饮食底物与宿主之间的复杂相互作用来调节的肝脏和其他器官系统中的遗传因素。但是，调节TMAO的生物学途径肝产生的水平以及这些因素是否与饮食中的胆碱或L-肉碱相互作用以影响动脉粥样硬化尚不清楚。此外，关于生物学的许多问题仍未得到答复 TMAO促进动脉粥样硬化的机制以及TMAO和CVD之间的关联是否在人类中代表了因果关系。本文提出的综合策略直接解决这些问题知识的关键差距。在特定的目标1中，我们将确定促进的生物学机制 TMAO的动脉粥样硬化特性使用我们最近为此创建的一般修饰的小鼠模型含黄素单加氧酶3（FMO3）的缺乏，这是负责肝tmao的主要酶生产。 FMO3无效的小鼠将在上下文中全面地为主动脉病变发育进行全面表征动脉粥样硬化的高胆碱饮食。我们还将在小鼠模型确定体内炎症过程是否在tmao上促进血管壁通过NF-B途径介导。在特定目标2中，我们将使用比较系统具有> 41,000名受试者和〜100个近交小鼠菌株的遗传学策略，以识别遗传因素通过主要作用和/或基因界相互作用影响等离子体TMAO的水平。这些结果在> 500,000名受试者中，将使用同步映射研究用于硅和门德尔随机分析建立TMAO与CVD风险之间的因果关系。结合结合，拟议的研究具有 1）阐明TMAO促进动脉粥样硬化的炎症机制； 2）确定CVD的新颖和临床重要危险因素的遗传决定剂，并提供更好地理解基因与饮食因素之间的相互作用如何介导血浆TMAO的变化水平和CVD风险； 3）提供遗传证据表明TMAO和CVD之间的关系是因果关系。综上所述，我们的研究结果将支持靶向TMAO是一种新的疗法的观念可能降低CVD风险的策略与已知的生物途径和危险因素无关。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diet, Fecal Microbiome, and Trimethylamine N-Oxide in a Cohort of Metabolically Healthy United States Adults.

DOI：
10.3390/nu14071376
发表时间：
2022-03-25
期刊：
Nutrients
影响因子：
5.9
作者：
通讯作者：

Trimethylamine N-Oxide Response to a Mixed Macronutrient Tolerance Test in a Cohort of Healthy United States Adults.

DOI：
10.3390/ijms24032074
发表时间：
2023-01-20
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
James, Kristen L.;Gertz, Erik R.;Kirschke, Catherine P.;Allayee, Hooman;Huang, Liping;Kable, Mary E.;Newman, John W.;Stephensen, Charles B.;Bennett, Brian J.
通讯作者：
Bennett, Brian J.