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:10365684
- 负责人:
- 金额:$ 72.61万
- 依托单位:
- 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:
- 关键词:AdultAffectApolipoprotein EAtherosclerosisBile AcidsBioinformaticsBloodBlood VesselsCardiovascular DiseasesCardiovascular systemCellsChildDevelopmentDiseaseEcologyExposure toFamilyFoam CellsGPBAR1 geneGerm-FreeHumanHypercapniaHypoxiaIn VitroKnock-outKnockout MiceKnowledgeLaboratoriesLeadLightLow-Density LipoproteinsLung diseasesMacrophage ActivationMediatingMetabolismMetagenomicsMouse StrainsMusMyocardial InfarctionObesityObstructive Sleep ApneaPeritoneal MacrophagesPlayPopulationPrimary Cell CulturesRisk FactorsRoleSleep DisordersTechnologyTestingatherogenesisbasebile saltscardiovascular disorder preventioncardiovascular risk factorgut bacteriagut microbiomeimprovedin vivoinsightmacrophagemetabolomemetabolomicsmicrobialmicrobiomemicrobiotamicrobiota metabolitesnew therapeutic targetnoveloxidized low density lipoproteinpreventreceptorreverse cholesterol transportuptake
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.
摘要
阻塞性睡眠呼吸暂停(OSA)是一种常见的疾病,影响超过10%的成年人和2-3%的人。
在美国的儿童。阻塞性睡眠呼吸暂停被认为是心血管疾病发生的独立危险因素
和肺部疾病,但其潜在的机制仍在很大程度上未知。特别是,
间歇性低氧和高碳酸血症(IHC,OSA的组成部分)在诱导或促进
心血管疾病仍然不清楚。测序技术和微生物及
代谢组学生物信息学揭示了肠道微生物组与
心血管疾病由于阻塞性睡眠呼吸暂停是这些疾病的一个关键危险因素,我们的初步研究
已经证明IHC改变了肠道微生物组的生态,并对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异性改变,
这些变化可促进动脉粥样硬化。事实上,我们已经获得了强有力的候选微生物家族,
和代谢物,可以影响血管的完整性在IHC。例如,我们发现a)IHC
加速ApoE-/-小鼠中动脉粥样硬化的形成; B)IHC改变ApoE-/-小鼠的肠道微生物组生态学,
科,如疣微菌科、瘤胃球菌科和丹毒丝菌科;和
微生物衍生的代谢物(如胆汁盐(BA))。在当前应用中,我们关注这些
微生物群和代谢物候选物,以研究它们在动脉粥样硬化中的作用。首先,我们将分离出特定的
通过IHC处理改变的肠道微生物菌株,并确定这些特定微生物
使用无菌ApoE-/-小鼠体内心血管疾病发展中的一种或多种菌株,
在我们的实验室里创造和建立。其次,我们将描述主要胆汁酸受体的作用
(i.e., FXR和TGR 5)介导候选胆汁酸在IHC诱导的心血管疾病中的作用
使用ApoE-/-/FXR-/-和ApoE-/-/TGR 5-/-双敲除小鼠品系以及携带ApoE-/-/FXR-/-和ApoE-/-/TGR 5-/-的小鼠品系,
ApoE-/-背景下FXR和TGR 5的细胞特异性条件性缺失。第三,我们将剖析
特异性IHC改变的胆汁酸作用的潜在机制(即,TβMCA和UDCA)诱导的
使用来源于ApoE-/-小鼠的原代细胞培养物体外巨噬细胞泡沫细胞形成
/FXR-/-和Apoe-/-/TGR 5-/-双缺失。该项目将描述新的机制,调节OSA-
诱导的心血管疾病,并提供潜在的新的目标和战略,以改善治疗或
预防疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gabriel G Haddad其他文献
Heart Rate Variability during Respiratory Pauses in Puppies and Dogs
幼犬和犬呼吸暂停期间的心率变异性
- DOI:
10.1203/00006450-198709000-00014 - 发表时间:
1987-09-01 - 期刊:
- 影响因子:3.100
- 作者:
Gabriel G Haddad;Huajin J Jeng;Tze L Lai - 通讯作者:
Tze L Lai
The QT Interval in Aborted Sudden Infant Death Syndrome Infants
婴儿猝死综合征夭折婴儿的 QT 间期
- DOI:
10.1203/00006450-197902000-00010 - 发表时间:
1979-02-01 - 期刊:
- 影响因子:3.100
- 作者:
Gabriel G Haddad;Mary Anne F Epstein;Ralph A Epstein;Norman M Mazza;Robert B Mellins;Ehud Krongrad - 通讯作者:
Ehud Krongrad
The Effect of Oxygen Deprivation on the Cell Cycle of Drosophila melanogaster Embryos
缺氧对黑腹果蝇胚胎细胞周期的影响
- DOI:
10.1203/00006450-199904020-00319 - 发表时间:
1999-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Benjamin H Huffard;Robert M Douglas;Gabriel G Haddad - 通讯作者:
Gabriel G Haddad
Plasma β-Casomorphin-7 Immunoreactive Peptide Increases after Milk Intake in Newborn but not in Adult Dogs
新生犬摄入牛奶后血浆β-酪啡肽-7 免疫反应性肽增加,但成年犬则没有。
- DOI:
10.1203/00006450-198907000-00011 - 发表时间:
1989-07-01 - 期刊:
- 影响因子:3.100
- 作者:
Malathy Singh;Carol L Rosen;Kwen Jen Chang;Gabriel G Haddad - 通讯作者:
Gabriel G Haddad
972 THE QT INTERVAL IN ABORTED SIDS INFANTS
972 aborted SIDS 婴儿的 QT 间期
- DOI:
10.1203/00006450-197804001-00978 - 发表时间:
1978-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Gabriel G Haddad;Mary A F Epstein;Ralph A Epstein;Norman M Mazza;Robert B Mellins - 通讯作者:
Robert B Mellins
Gabriel G Haddad的其他文献
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{{ truncateString('Gabriel G Haddad', 18)}}的其他基金
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:
10544020 - 财政年份:2022
- 资助金额:
$ 72.61万 - 项目类别:
Effect of methadone on the developmental properties of human brain organoids
美沙酮对人脑类器官发育特性的影响
- 批准号:
10442944 - 财政年份:2022
- 资助金额:
$ 72.61万 - 项目类别:
Effect of methadone on the developmental properties of human brain organoids
美沙酮对人脑类器官发育特性的影响
- 批准号:
10618375 - 财政年份:2022
- 资助金额:
$ 72.61万 - 项目类别:
Developing Diverse Physician-Investigator Leaders for the Future of Child Health
为儿童健康的未来培养多元化的医师研究员领导者
- 批准号:
10226721 - 财政年份:2021
- 资助金额:
$ 72.61万 - 项目类别:
Mechanisms underlying Notch function in hypoxia
缺氧时Notch功能的机制
- 批准号:
10302526 - 财政年份:2021
- 资助金额:
$ 72.61万 - 项目类别:
Developing Diverse Physician-Investigator Leaders for the Future of Child Health
为儿童健康的未来培养多元化的医师研究员领导者
- 批准号:
10610939 - 财政年份:2021
- 资助金额:
$ 72.61万 - 项目类别:
Developing Diverse Physician-Investigator Leaders for the Future of Child Health
为儿童健康的未来培养多元化的医师研究员领导者
- 批准号:
10374925 - 财政年份:2021
- 资助金额:
$ 72.61万 - 项目类别:
Genetic Mechanisms Regulating Hypoxia Tolerance in the Brain
调节大脑缺氧耐受性的遗传机制
- 批准号:
9894142 - 财政年份:2020
- 资助金额:
$ 72.61万 - 项目类别:
Molecular Basis of Hypoxia-Induced Excessive Erythrocytosis
缺氧引起红细胞增多症的分子基础
- 批准号:
10443584 - 财政年份:2019
- 资助金额:
$ 72.61万 - 项目类别:
Molecular Basis of Hypoxia-Induced Excessive Erythrocytosis
缺氧引起红细胞增多症的分子基础
- 批准号:
10204098 - 财政年份:2019
- 资助金额:
$ 72.61万 - 项目类别:
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