Obstructive sleep apnea, the microbiome and cardiovascular disease

阻塞性睡眠呼吸暂停、微生物组和心血管疾病

• 批准号: 10365684
• 负责人: Gabriel G Haddad
• 金额: $ 72.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365684
• 关键词: Adult; Affect; Apolipoprotein E; Atherosclerosis; Bile Acids; Bioinformatics; Blood; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Child; Development; Disease; Ecology; Exposure to; Family; Foam Cells; GPBAR1 gene; Germ-Free; Human; Hypercapnia; Hypoxia; In Vitro; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Light; Low-Density Lipoproteins; Lung diseases; Macrophage Activation; Mediating; Metabolism; Metagenomics; Mouse Strains; Mus; Myocardial Infarction; Obesity; Obstructive Sleep Apnea; Peritoneal Macrophages; Play; Population; Primary Cell Cultures; Risk Factors; Role; Sleep Disorders; Technology; Testing; atherogenesis; base; bile salts; cardiovascular disorder prevention; cardiovascular risk factor; gut bacteria; gut microbiome; improved; in vivo; insight; macrophage; metabolome; metabolomics; microbial; microbiome; microbiota; microbiota metabolites; new therapeutic target; novel; oxidized low density lipoprotein; prevent; receptor; reverse cholesterol transport; uptake

ABSTRACT Obstructive sleep apnea (OSA) is a common condition affecting >10% of the adult population and 2-3% of children in the USA. OSA is considered as an independent risk factor for the development of cardiovascular and lung disorders but the underlying mechanisms are still largely unknown. In particular, the role of intermittent hypoxia and hypercapnia (IHC, the integral components of OSA) in inducing or promoting cardiovascular conditions remains obscure. Recent advances in sequencing technology and microbial and metabolomic bioinformatics have shed light on an important relation between the gut microbiome and cardiovascular diseases. Since OSA is a critical risk factor for these disorders, and our preliminary studies have demonstrated that IHC alters the ecology of gut microbiome and have a strong impact on metabolism, we hypothesize that IHC induces specific alterations in the gut microbiome and microbial-derived metabolites, and these changes causally promote atherosclerosis. Indeed, we have obtained strong candidate microbial families and metabolites that can affect vascular integrity under IHC. For example, we have found that a) IHC accelerates the formation of atherosclerosis in ApoE-/- mice; b) IHC changes the gut microbiome ecology of families such as Verrucomicrobiaceae, Ruminococcaceae and Erysipelotrichaceae; and c) IHC alters microbial-derived metabolites (such as bile salts (BAs)). In the current application, we focus on these microbiota and metabolite candidates to investigate their role in atherosclerosis. First, we will isolate specific gut microbial strains that were altered by IHC treatment and determine the role of these specific microbial strain(s) in the development of cardiovascular disease in vivo using germ-free ApoE-/- mice that were currently created and established in our laboratory. Second, we will delineate the role of the major bile acid receptors (i.e., FXR and TGR5) in mediating the effect of candidate bile acids in IHC-induced cardiovascular disease in vivo using ApoE-/-/FXR-/- and ApoE-/-/TGR5-/- double knockout mice strains as well as the mice strains carrying cell specific conditional deletion of FXR and TGR5 on ApoE-/- background. And third, we will dissect the mechanisms underlying the role of specific IHC-altered bile acids (i.e., TβMCA and UDCA) in IHC-induced macrophage foam cell formation in vitro using primary cell cultures that are derived from mice with ApoE-/- /FXR-/- and ApoE-/-/TGR5-/- double deletion. This project will delineate novel mechanisms regulating OSA- induced cardiovascular disease and provide potential novel targets and strategies to improve treatment or prevent disease.

摘要 阻塞性睡眠呼吸暂停(OSA)是一种常见的疾病，影响10%的成年人和2-3%的成年人 在美国的儿童。OSA被认为是心血管疾病发生的独立危险因素 和肺部疾病，但其潜在机制在很大程度上仍不清楚。具体地说， 间歇性低氧和高碳酸血症(IHC)在诱导或促进OSA中的作用 心血管疾病仍不清楚。测序技术及微生物和生物多样性研究的最新进展 代谢组生物信息学揭示了肠道微生物组和肠道微生物组之间的重要关系 心血管疾病。由于OSA是这些疾病的关键风险因素，我们的初步研究 已经证明IHC改变了肠道微生物群的生态，并对新陈代谢产生了强烈的影响，我们 假设IHC诱导肠道微生物组和微生物衍生代谢物的特定变化，以及 这些变化必然会促进动脉粥样硬化。事实上，我们已经获得了强有力的候选微生物家族 以及在IHC下可能影响血管完整性的代谢物。例如，我们发现a)IHC 加速ApoE-/-小鼠动脉粥样硬化的形成；b)IHC改变ApoE-/-小鼠肠道微生物生态 如微生物科、瘤胃球菌科和毛霉科；以及c)IHC改变 微生物衍生的代谢物(如胆盐(BAS))。在当前的应用程序中，我们主要关注以下内容 微生物区系和代谢物候选以研究它们在动脉粥样硬化中的作用。首先，我们将隔离特定的 经IHC处理改变的肠道微生物菌株，并确定这些特定微生物的作用 利用无菌载脂蛋白E-/-小鼠体内研究S株在心血管疾病发展中的作用 在我们实验室创建和建立的。第二，我们将描述主要胆汁酸受体的作用。 (FXR和TGR5)在IHC诱导的心血管疾病中对候选胆汁酸的影响 体内使用ApoE-/-/FXR-/-和ApoE-/-/TGR5-/-双基因敲除小鼠品系以及携带 ApoE-/-背景上FXR和TGR5的细胞特异性条件性缺失。第三，我们将剖析 特异性胆汁酸(即T-β、MCA和UDCA)在IHC诱导中的作用机制 载脂蛋白E-/-小鼠来源的原代细胞在体外形成巨噬细胞泡沫细胞 /FXR-/-和ApoE-/-/TGR5-/-双删除。这个项目将勾勒出监管OSA的新机制- 诱发心血管疾病，并提供潜在的新目标和战略来改善治疗或 预防疾病。