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
• 负责人: Sanjana Dayal
• 金额: $ 30.96万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8978849
• 关键词: Adoptive Transfer; Aging; Antibodies; Biological Assay; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Clinical; Coagulation Process; Collaborations; Comorbidity; Data; Deep Vein Thrombosis; Elderly; Enzymes; Epidemiologic Studies; Epitopes; Event; Exhibits; Generations; Genetic; Genetically Engineered Mouse; Goals; Healthcare; Human; Hydrogen Peroxide; Hyperactive behavior; Incidence; Integrins; Life Expectancy; Mediating; Mediator of activation protein; Morbidity - disease rate; Mus; Myocardial Infarction; NADPH Oxidase; Oxidases; Pathway interactions; Peptides; Peroxides; Pilot Projects; Platelet Activation; Population; Predisposition; Prevention; Pulmonary Embolism; Reactive Oxygen Species; Relative (related person); Research Personnel; Role; Source; Stress; Stroke; Superoxides; Surface; Testing; Thrombosis; Thrombus; Transgenic Organisms; Up-Regulation; Venous; Venous Thrombosis; Wild Type Mouse; Work; age effect; age related; aged; aging population; artery occlusion; base; genetic approach; glutathione peroxidase; human subject; in vivo; inhibitor/antagonist; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; older patient; overexpression; prevent; public health relevance; research study

 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(申请人提供)：血栓并发症，如心血管疾病和中风，是我们老龄化人口发病率和死亡率的主要原因。尽管衰老与血栓形成有很强的临床相关性，但老年人血栓形成的机制尚不清楚。在最近的一项研究中，我们证明了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，衰老小鼠出现了血小板内过氧化氢(H_2O_2)水平升高和血小板过度活动(整合素AIIBü3活性增强)。重要的是，消除过氧化氢的遗传方法可以防止衰老小鼠的血小板过度活动，这表明过氧化氢是一个关键的介体。重要的是，我们在人类受试者中的初步研究表明，来自老年人的血小板表现出过氧化氢介导的高活性。这项应用的目的是确定导致过氧化氢在血小板中积累的上游机制，并确定预防过氧化氢介导的血小板过度活性是否可以减少与衰老相关的血栓易感性的增加。我们的中心假设是，衰老通过增强血小板激活导致动脉和静脉血栓易感性增加，该途径包括含有NOX2的NADPH氧化酶产生超氧化物，随后超氧化物歧化酶1(SOD1)将超氧化物转化为过氧化氢，导致过氧化氢诱导的血小板激活增强。这一假说的理论基础是含有NOX2的NADPH氧化酶是血小板活性氧物种的主要来源，我们最近的研究表明，老年小鼠血小板中NADPH氧化酶和SOD1的表达上调。目的1探讨NADPH氧化酶和SOD1在衰老过程中血小板过度激活中的作用机制。目的2将确定抑制过氧化氢介导的血小板过度活性是否足以降低随年龄增长的血栓易感性。研究将利用一种新的小鼠模型，在移植老年或年轻小鼠的血小板之前，内源性血小板被免疫耗尽，从而在没有宿主血小板潜在混杂影响的情况下，评估供者血小板对动脉闭塞和静脉血栓的影响。AIM 3将评估老年人血小板过度活跃及其血栓形成的后果。了解随着年龄增长的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，以最大限度地减少老年人的血管衰退。