Circulating Age-related Lipid Mediators in Thrombosis

血栓形成中循环年龄相关脂质介质

• 批准号: 7340884
• 负责人: Thomas M McIntyre
• 金额: $ 54.04万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340884
• 关键词: Abnormal Platelet; Accounting; Acids; Age; Aging; Aging-Related Process; Agonist; Animal Model; Animals; Antioxidants; Apoptosis; Aspirin; Blood Circulation; Blood Platelets; CD36 gene; Caspase; Cell surface; Cells; Chronic; Code; Condition; Data; Dodecenoic Acid; Esters; Event; Exposure to; Female; Gender; Human; Immune system; Inflammation; Inflammatory; Intervention; Lecithin; Lipids; Mediator of activation protein; Membrane; Messenger RNA; Mitochondria; Modeling; Molecular; Mus; Numbers; Organ; Organism; Pathologic; Permeability; Phenotype; Phosphatidylserines; Phospholipids; Phosphotransferases; Platelet Activating Factor; Platelet Activation; Polyunsaturated Fatty Acids; Process; Production; Proteins; RNA; RNA Splicing; Reactive Oxygen Species; Research Personnel; Resistance; Resveratrol; Risk; Role; Route; Signal Pathway; Signal Transduction; Stimulus; Surface; TLR2 gene; TLR4 gene; Testing; Thromboembolism; Thromboplastin; Thrombosis; Thromboxane A2; Thrombus; Translating; Translation Process; Translations; Venous; Venous Thrombosis; age related; aged; cyclooxygenase 2; dietary supplements; doxorubicin/fluorouracil/melphalan protocol; feeding; human study; improved; in vivo; kinase inhibitor; lipid mediator; male; novel; oxidation; oxidized low density lipoprotein; platelet activating factor receptor; receptor; response; stem; theories

DESCRIPTION (provided by applicant): Aging is associated with an increased risk of venous thrombosis, but we do not understand the factors that connect aging to an increasing propensity for pathologic thrombotic events. The oxidative theory of aging has stout support in describing age-related decreases in organ function; it is less apparent that this pro-oxidative state underlies venous thrombotic events associated with aging. Recent appreciation for a role of platelets in these thrombi, a recent understanding of a novel mode of platelet activation, and the presence of agonists in the circulation of aged animals may provide a molecular understanding of age-related changes that promote venous thrombosis. Platelets have stored RNA that encodes tissue factor, and other relevant proteins, and appropriate stimuli causes activation-dependent splicing and translation that reprograms the phenotype of the platelet. One result of this is strong tissue factor expression on platelets, along with phosphatidylserine expression and microparticle shedding. Mitochondrial dysfuction accounts for the latter processes. Aging is associated with a pro-oxidative state, and the primary target of oxidizing radicals are the polyunsaturated fatty acids esterifed in membrane phospholipids. Some phospholipid oxidation products structurally resemble PAF and potently activate all cells of the innate immune system. Others are transported into cells and depolarize mitochondria, initiate caspase dependent apoptosis, and allow phosphatidylserine to be displayed on the cell surface. These agonists are potent, and their formation is unregulated. Resveratrol is an anti-oxidant that additionally protects mitochondria and reduces signaling of atypical platelet receptors. We find oxidized phospholipids in the circulation of aged animals that are PAF receptor agonists and ones that potently depolarize mitochondria. The levels of these rival that of chronic inflammation. We propose to describe these agents, and manipulate their levels in 4 aims: Define age- and gender-related accumulation of circulating thrombotic/depolarizing mediators; Molecularly define the effect of oxidized phospholipids on platelets; Define pro-thrombotic signal transduction events downstream of receptors that reprogram the platelet phenotype; Determine whether resveratrol intervention suppresses age-related venous thrombosis.

描述（由申请人提供）：衰老与静脉血栓形成风险增加相关，但我们不了解将衰老与病理性血栓事件倾向增加联系起来的因素。衰老的氧化理论在描述与年龄相关的器官功能下降方面有强有力的支持。这种促氧化状态是与衰老相关的静脉血栓事件的基础，这一点不太明显。最近对血小板在这些血栓中的作用的认识、对血小板激活的新模式的最新了解以及老年动物循环中激动剂的存在可能提供对促进静脉血栓形成的年龄相关变化的分子理解。 血小板储存了编码组织因子和其他相关蛋白质的RNA，适当的刺激会引起激活依赖性剪接和翻译，从而重新编程血小板的表型。其结果之一是血小板上强烈的组织因子表达，以及磷脂酰丝氨酸表达和微粒脱落。线粒体功能障碍是后一过程的原因。 衰老与促氧化状态有关，氧化自由基的主要目标是膜磷脂中酯化的多不饱和脂肪酸。一些磷脂氧化产物在结构上类似于 PAF，可有效激活先天免疫系统的所有细胞。其他物质被转运到细胞中并使线粒体去极化，启动半胱天冬酶依赖性细胞凋亡，并允许磷脂酰丝氨酸在细胞表面展示。这些激动剂是有效的，并且它们的形成不受管制。白藜芦醇是一种抗氧化剂，还能保护线粒体并减少非典型血小板受体的信号传导。 我们在老年动物的循环中发现氧化磷脂，它们是 PAF 受体激动剂，并且可以有效使线粒体去极化。这些的水平与慢性炎症的水平相当。我们 提议描述这些药物，并在 4 个目标中控制它们的水平： 定义循环血栓/去极化介质与年龄和性别相关的积累；从分子角度定义氧化磷脂对血小板的影响；定义重新编程血小板表型的受体下游的促血栓信号转导事件；确定白藜芦醇干预是否可以抑制与年龄相关的静脉血栓形成。