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: 9268549
• 负责人: Sanjana Dayal
• 金额: $ 31.26万
• 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/9268549
• 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; 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; Pharmacology; Pilot Projects; Platelet Activation; Population; Predisposition; Prevention; Pulmonary Embolism; Reactive Oxygen Species; 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; epidemiology study; experimental study; genetic approach; glutathione peroxidase; human subject; in vivo; inhibitor/antagonist; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; older patient; overexpression; prevent; public health relevance

 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（由适用提供）：血栓形成并发症，例如心血管疾病和中风是我们老龄化人群中发病率和死亡率的主要原因。尽管衰老和血栓形成之间存在牢固的临床关联，但在古老的人中，血栓形成的机制尚不清楚。在最近的一项研究中，我们表明老年小鼠表现出增加对血栓形成的敏感性。我们的发现还表明，老化的小鼠会发展出众多的细胞内氢过氧化氢（H2O2）水平和血小板多动（增加的整联蛋白AIIBß3激活）。重要的是，消除H2O2的遗传方法可防止老年小鼠的血小板多动症，这表明H2O2是关键的介体。重要的是，我们在人类受试者中的试点研究表明，来自老年人的过氧化物介导的多动症的血小板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介导的血小板介导的血小板降低了降低了衰老的降低了降低了降低了降低了促凝结剂的肿瘤敏感性。我们的核心假设是，衰老通过在途径中增强血小板激活增加了人工体和静脉血栓敏感性，包括通过含有NADPH氧化物的Nox2产生超氧化物，然后通过超氧化物歧义酶1（SOD1）转化超氧化物将超氧化物转化为H2O2（SOD1），从而导致H2O2诱导的增强型高素化型的增强型H2O2。该假设的理由是，含有NADPH氧化物的NOX2是血小板活性氧的主要来源，而我们最近的研究表明，来自老年小鼠的血小板中NADPH氧化物和SOD1的上调。 AIM 1将确定NADPH氧化物和SOD1在衰老中血小板过度激活中的机械作用。 AIM 2将确定H2O2介导的血小板多动的抑制是否足以降低血栓形成衰老的敏感性。研究将利用一种新型的小鼠模型，在该模型中，内源性血小板在从老年或年轻小鼠转移血小板之前进行免疫部门，从而评估供体血小板在没有宿主血小板潜在混淆作用的情况下对供体闭塞和静脉血栓形成的影响。 AIM 3将评估老年人的血小板及其血栓形成后果的多动症。了解血小板激活有助于血栓敏感的机制有可能揭示新的治疗策略，以最大程度地减少老年血管下降。