Early Life Stress and Cardiovascular Disease Risk: Identifying the Role of Microbial Metabolites
早期生活压力和心血管疾病风险:确定微生物代谢物的作用
基本信息
- 批准号:10739155
- 负责人:
- 金额:$ 17.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdolescenceAdolescentAdolescent and Young AdultAdultAgeAortaAttenuatedBig DataBioinformaticsBiological AssayBlood VesselsButyratesCardiovascular DiseasesCardiovascular PhysiologyCardiovascular systemCause of DeathChildChronic DiseaseChronic Kidney FailureClostridiaceaeDataDevelopmentDietEarly InterventionEarly identificationEndogenous FactorsExposure toFamilyFermentationFunctional disorderFutureGoalsHealthHouseholdHypertensionImmuneImpairmentIndividualInterventionKnowledgeLactobacillaceaeLifeLinkMachine LearningMeasurementMeasuresMediatingMediationMediatorMental disordersMetabolicMusNeurologicPathway interactionsPeripheral ResistancePhasePhenotypePlayProductionPropionatesPublishingRecording of previous eventsResearchRiskRisk FactorsRodent ModelRoleStressful EventSuperoxidesSupplementationSystemTechniquesTestingTime-restricted feedingTissuesUnited StatesVascular DiseasesVolatile Fatty AcidsWomanarterial stiffnessblood pressure controlcardiovascular disorder riskcardiovascular risk factordata integrationdisorder riskdysbiosisearly experienceearly life stressendothelial dysfunctionexperiencefatty acid supplementationgut microbiotain vivomRNA Expressionmaternal separationmetabolomicsmetagenomic sequencingmicrobialmouse modelneglectneonatenoveloffspringpediatric traumaprotein expressionreceptorreceptor expressionsingle-cell RNA sequencingskillsstress reduction
项目摘要
PROJECT SUMMARY/ABSTRACT:
Exposure to early life stress (ELS), including abuse, neglect, and household dysfunction, significantly
increases the risk of mental illness, chronic kidney disease, and cardiovascular disease (CVD) later in life. The
previously characterized effects ELS and chronic disease development in adults may have their origins in ELS-
dependent effects on composition and functions of the gut microbiota. The gut microbiota interact directly with
the host’s immune and neurological systems and microbial derived metabolites have been shown to mediation
cardiovascular function. My recently published research using a mouse model of ELS has determined that ELS
alters the gut microbiota independent of maternal inheritance. This suggests ELS-medicated endogenous
factors within the offspring are responsible for the ELS microbial phenotype. However, it remains unknown
whether ELS-mediated changes in the gut microbiota play a direct role in the genesis risk factors for CVD. This
proposal will address these knowledge gaps by identifying ELS-medicated factors that regulate the gut
microbiota and elucidating microbial-mediated pathways that lead to increased CVD risk due to ELS.
Adolescents and young adults with ELS have increased arterial stiffness and systemic vascular
resistance. Using an established mouse model of ELS involving maternal separation, our novel data indicate
that ELS is also associated with increased arterial stiffness in adolescent and adult mice. Furthermore, ELS
induces superoxide production and endothelial dysfunction in adult mice. This suggests that vascular
dysfunction is an important mediator of ELS-induced CVD risk. Our new data in mice show that ELS leads to
reduced gut microbial diversity, lower circulating short-chain-fatty acids (SCFAs), and impaired gut barrier
function during adolescence. Gut microbial diversity is negatively associated with arterial stiffness in women
and reduced SCFAs are associated with hypertension and impaired gut barrier function. This suggests a role
for the gut microbiota in ELS-induced vascular dysfunction, though exact mechanisms remain undefined.
Therefore, the overall goal of this proposal is to elucidate mechanisms by which microbial metabolites
mediate ELS-induced aortic stiffening and endothelial dysfunction and examine the potential of diet in the early
intervention of CVD risk.
项目总结/摘要:
暴露于早期生活压力(ELS),包括虐待,忽视和家庭功能障碍,
会增加日后患精神疾病、慢性肾病和心血管疾病(CVD)的风险。的
先前描述的ELS效应和成人慢性疾病的发展可能起源于ELS-
对肠道微生物群的组成和功能的依赖性影响。肠道微生物群直接与
宿主的免疫和神经系统以及微生物衍生的代谢物已被证明是介导的
心血管功能我最近发表的使用ELS小鼠模型的研究已经确定ELS
改变肠道微生物群而不依赖于母体遗传。这表明ELS介导的内源性
后代中的因子负责ELS微生物表型。然而,
ELS介导的肠道微生物群变化是否在CVD的发生风险因素中起直接作用。这
一项提案将通过确定调节肠道的ELS药物因子来解决这些知识缺口
微生物群和阐明微生物介导的途径,导致增加的CVD风险,由于ELS。
患有ELS的青少年和年轻人的动脉僵硬度和全身血管硬化增加。
阻力使用一个建立的ELS小鼠模型,包括母体分离,我们的新数据表明,
ELS也与青少年和成年小鼠动脉硬化增加有关。此外,ELS
诱导成年小鼠产生超氧化物和内皮功能障碍。这表明,
功能障碍是ELS诱导的CVD风险的重要介质。我们在小鼠身上的新数据表明,ELS导致
肠道微生物多样性减少,循环短链脂肪酸(SCFA)减少,肠道屏障受损
青春期的功能。肠道微生物多样性与女性动脉僵硬度呈负相关
SCFA减少与高血压和肠屏障功能受损有关。这表明
对于ELS诱导的血管功能障碍中的肠道微生物群,尽管确切的机制尚未确定。
因此,本提案的总体目标是阐明微生物代谢产物
介导ELS诱导的主动脉硬化和内皮功能障碍,并检查饮食在早期
干预心血管疾病风险。
项目成果
期刊论文数量(0)
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