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

基本信息

批准号：
10544020
负责人：
Gabriel G Haddad
金额：
$ 72.26万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10544020
关键词：
Acceleration 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 Low-Density Lipoproteins Lung diseases Macrophage 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 Stroke Technology Testing atherogenesis bile salts cardiovascular disorder prevention cardiovascular risk factor gut bacteria gut microbiome improved in vivo insight metabolome metabolomics microbial microbiome microbiota new therapeutic target novel oxidized low density lipoprotein prevent receptor reverse cholesterol transport uptake

项目摘要

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）是一种常见状况，影响成年人口> 10％和2-3％美国的儿童。 OSA被认为是心血管发展的独立危险因素和肺部疾病，但潜在的机制在很大程度上是未知的。特别是诱导或促进心血管状况仍然晦涩。测序技术和微生物的最新进展以及代谢组生物信息学已经阐明了肠道微生物组与心血管疾病。由于OSA是这些疾病和我们的初步研究的关键危险因素已经证明IHC改变了肠道微生物组的生态，并对代谢产生强烈的影响，我们假设IHC诱导肠道微生物组和微生物衍生的代谢产物的特定变化，以及这些变化有可能促进动脉粥样硬化。确实，我们获得了强大的候选微生物家族以及可能影响IHC下血管完整性的代谢产物。例如，我们发现a）IHC 加速APOE - / - 小鼠的动脉粥样硬化的形成； b）IHC改变了肠道微生物组的生态绿核细菌科，ruminococcacaceae和erysipelotrichaceae等家庭； c）IHC改变了微生物衍生的代谢产物（例如胆汁销售（BAS））。在当前的应用程序中，我们专注于这些微生物群和代谢物候选者研究其在动脉粥样硬化中的作用。首先，我们将特定于特定 IHC处理改变并确定这些特定微生物的作用的肠道微生物菌株使用无细菌apoE - / - 当前是体内心血管疾病发展的菌株在我们的实验室中创建和建立。其次，我们将描述主要的胆汁酸接收器的作用（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中使用apoe - / - /fxr-/ - 和apoE-/ - / - / - / - 双敲除小鼠菌株以及携带的小鼠菌株 apoE-/ - 背景上FXR和TGR5的细胞特异性条件删除。第三，我们将剖析特定IHC改变的胆汁酸（即TβMCA和UDCA）在IHC诱导的巨噬细胞泡沫细胞在体外形成，使用源自apoe的小鼠的原代细胞培养物 - / - /fxr - / - 和apoe - / - /tgr5 - / - 双重删除。该项目将描述调节OSA-的新型机制诱发心血管疾病，并提供了潜在的新目标和策略来改善治疗或预防疾病。