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.

抽象的 阻塞性睡眠呼吸暂停 (OSA) 是一种常见疾病，影响超过 10% 的成年人口和 2-3% 美国儿童的数量。 OSA被认为是心血管疾病发生的独立危险因素 和肺部疾病，但其潜在机制仍然很大程度上未知。特别是，角色 间歇性缺氧和高碳酸血症（IHC，OSA 的组成部分）在诱导或促进中的作用 心血管疾病仍不清楚。测序技术和微生物的最新进展 代谢组生物信息学揭示了肠道微生物组与肠道菌群之间的重要关系 心血管疾病。由于 OSA 是这些疾病的关键危险因素，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强烈影响，我们 假设 IHC 会诱导肠道微生物组和微生物衍生代谢物发生特定改变，并且 这些变化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 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 改变肠道微生物组生态 科，例如 Verrucomicrobiaceae、Ruminococcaceae 和 Erysipelotrichaceae； c) IHC 改变 微生物衍生的代谢物（例如胆盐（BA））。在当前的应用中，我们主要关注这些 微生物群和代谢候选物，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 通过 IHC 治疗改变的肠道微生物菌株并确定这些特定微生物的作用 使用无菌 ApoE-/- 小鼠体内开发心血管疾病的菌株 在我们的实验室创建和建立。其次，我们将描述主要胆汁酸受体的作用 （即 FXR 和 TGR5）在介导候选胆汁酸在 IHC 诱导的心血管疾病中的作用 体内使用 ApoE-/-/FXR-/- 和 ApoE-/-/TGR5-/- 双敲除小鼠品系以及携带 在 ApoE-/- 背景上细胞特异性条件性删除 FXR 和 TGR5。第三，我们将剖析 特定 IHC 改变的胆汁酸（即 TβMCA 和 UDCA）在 IHC 诱导的作用中的作用机制 使用源自 ApoE-/- 小鼠的原代细胞培养物在体外形成巨噬细胞泡沫细胞 /FXR-/- 和 ApoE-/-/TGR5-/- 双重删除。该项目将描述调节 OSA 的新机制 诱发心血管疾病，并提供潜在的新靶点和策略来改善治疗或 预防疾病。