Peroxide mediated prothrombotic effects of aging
过氧化物介导的衰老促血栓形成作用
基本信息
- 批准号:9268549
- 负责人:
- 金额:$ 31.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-15 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adoptive TransferAgingAntibodiesBiological AssayBlood PlateletsBlood VesselsCardiovascular DiseasesClinicalCoagulation ProcessCollaborationsComorbidityDataDeep Vein ThrombosisElderlyEnzymesEpitopesEventExhibitsGenerationsGeneticGenetically Engineered MouseGoalsHealthcareHumanHydrogen PeroxideHyperactive behaviorIncidenceIntegrinsLife ExpectancyMediatingMediator of activation proteinMorbidity - disease rateMusMyocardial InfarctionNADPH OxidaseOxidasesPathway interactionsPeptidesPeroxidesPharmacologyPilot ProjectsPlatelet ActivationPopulationPredispositionPreventionPulmonary EmbolismReactive Oxygen SpeciesResearch PersonnelRoleSourceStressStrokeSuperoxidesSurfaceTestingThrombosisThrombusTransgenic OrganismsUp-RegulationVenousVenous ThrombosisWild Type MouseWorkage effectage relatedagedaging populationartery occlusionbaseepidemiology studyexperimental studygenetic approachglutathione peroxidasehuman subjectin vivoinhibitor/antagonistmortalitymouse modelnovelnovel strategiesnovel therapeutic interventionolder patientoverexpressionpreventpublic health relevance
项目摘要
DESCRIPTION (provided by applicant): Thrombotic complications such as cardiovascular diseases and stroke are a leading cause of morbidity and mortality in our aging population. Despite the strong clinical association between aging and thrombosis, the mechanisms of thrombosis in the elderly are not well understood. In a recent study we demonstrated that aged mice display increased susceptibility to thrombosis. Our findings also revealed that aged mice develop increased intra-platelet hydrogen peroxide (H2O2) levels and platelet hyperactivity (increased integrin aIIbß3 activation). Importantly, genetic approaches to eliminate H2O2 prevented platelet hyperactivity in aged mice, suggesting that H2O2 is a critical mediator. Importantly, our pilot studies in human subjects demonstrate that platelets from aged humans exhibit peroxide mediated hyperactivity The objectives of this application are to identify the upstream mechanism leading to accumulation of H2O2 in platelets and to determine whether prevention of H2O2-mediated platelet hyperactivity decreases aging-associated increased thrombotic susceptibility. Our central hypothesis is that aging results in increased arterial and venous thrombotic susceptibility via enhanced platelet activation in a pathway that includes generation of superoxide by a Nox2- containing NADPH oxidase, followed by conversion of superoxide to H2O2 by superoxide dismutase1 (SOD1), leading to H2O2-induced enhancement of platelet activation. The rationale for this hypothesis is that Nox2- containing NADPH oxidase is the major source of platelet reactive oxygen species, and our recent study demonstrated upregulation of NADPH oxidase and SOD1 in platelets from aged mice. Aim 1 will determine the mechanistic roles of NADPH oxidase and SOD1 in platelet hyperactivation in aging. Aim 2 will determine whether inhibition of H2O2-mediated platelet hyperactivity is sufficient to decrease thrombotic susceptibility with aging. Studies will utilize a novel mouse model in which endogenous platelets are immunodepleted prior to transfer of platelets from aged or young mice, allowing assessment of the effects of donor platelets on arterial occlusion and venous thrombosis in the absence of potential confounding effects of host platelets. Aim 3 will evaluate hyperactivity of platelets from aged humans and its thrombotic consequences. Understanding the mechanism by which platelet activation with aging contributes to thrombotic susceptibility has the potential to reveal new therapeutic strategies to minimize vascular decline in the elderly.
描述(由申请人提供):心血管疾病和中风等血栓并发症是老龄化人口发病和死亡的主要原因。尽管衰老与血栓形成之间存在密切的临床关联,但老年人血栓形成的机制尚不清楚。在最近的一项研究中,我们证明老年小鼠对血栓形成的易感性增加。我们的研究结果还显示,老年小鼠的血小板内过氧化氢 (H2O2) 水平升高,血小板过度活跃(整合素 aIIbß3 激活增加)。重要的是,消除 H2O2 的遗传方法可以防止老年小鼠的血小板过度活跃,这表明 H2O2 是一个关键的介质。重要的是,我们在人类受试者中的初步研究表明,老年人的血小板表现出过氧化物介导的过度活跃。本应用的目的是确定导致血小板中 H2O2 积累的上游机制,并确定预防 H2O2 介导的血小板过度活跃是否可以减少与衰老相关的血栓易感性增加。我们的中心假设是,衰老通过增强血小板活化导致动脉和静脉血栓易感性增加,其途径包括含有 Nox2 的 NADPH 氧化酶产生超氧化物,然后通过超氧化物歧化酶 1 (SOD1) 将超氧化物转化为 H2O2,从而导致 H2O2 诱导血小板活化增强。这一假设的基本原理是,含有 Nox2 的 NADPH 氧化酶是血小板活性氧的主要来源,我们最近的研究证明了老年小鼠血小板中 NADPH 氧化酶和 SOD1 的上调。目标 1 将确定 NADPH 氧化酶和 SOD1 在衰老过程中血小板过度活化中的机制作用。目标 2 将确定抑制 H2O2 介导的血小板过度活跃是否足以降低衰老过程中的血栓形成易感性。研究将利用一种新型小鼠模型,在从老年或年轻小鼠转移血小板之前,先将内源性血小板免疫耗竭,从而在不存在宿主血小板潜在混杂效应的情况下评估供体血小板对动脉闭塞和静脉血栓形成的影响。目标 3 将评估老年人血小板的过度活跃及其血栓形成的后果。了解随着年龄的增长血小板活化导致血栓易感性的机制有可能揭示新的治疗策略,以尽量减少老年人的血管衰退。
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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Sanjana Dayal其他文献
Sanjana Dayal的其他文献
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{{ truncateString('Sanjana Dayal', 18)}}的其他基金
Cellular effects of SARS-CoV-2 in mediating thrombotic susceptibility
SARS-CoV-2 在介导血栓易感性中的细胞作用
- 批准号:
10467274 - 财政年份:2022
- 资助金额:
$ 31.26万 - 项目类别:
Cellular effects of SARS-CoV-2 in mediating thrombotic susceptibility
SARS-CoV-2 在介导血栓易感性中的细胞作用
- 批准号:
10569568 - 财政年份:2022
- 资助金额:
$ 31.26万 - 项目类别:
Thrombogenic susceptibility in middle aged Veterans
中年退伍军人的血栓形成易感性
- 批准号:
10196967 - 财政年份:2020
- 资助金额:
$ 31.26万 - 项目类别:
Thrombogenic susceptibility in middle aged Veterans
中年退伍军人的血栓形成易感性
- 批准号:
10710160 - 财政年份:2020
- 资助金额:
$ 31.26万 - 项目类别:
Thrombogenic susceptibility in middle aged Veterans
中年退伍军人的血栓形成易感性
- 批准号:
10409685 - 财政年份:2020
- 资助金额:
$ 31.26万 - 项目类别:
Peroxide mediated prothrombotic effects of aging
过氧化物介导的衰老促血栓形成作用
- 批准号:
8978849 - 财政年份:2015
- 资助金额:
$ 31.26万 - 项目类别:
Peroxide mediated prothrombotic effects of aging (Supplement)
过氧化物介导的衰老促血栓形成作用(补充)
- 批准号:
9522272 - 财政年份:2015
- 资助金额:
$ 31.26万 - 项目类别:
Peroxide mediated prothrombotic effects of aging
过氧化物介导的衰老促血栓形成作用
- 批准号:
9144302 - 财政年份:2015
- 资助金额:
$ 31.26万 - 项目类别:
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