Circulating Age-related Lipid Mediators in 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形成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得到了有力的支持;这种促氧化状态是与衰老相关的静脉血栓形成事件的基础，这一点不太明显。最近的赞赏血小板在这些血栓中的作用，最近的理解一种新的模式的血小板活化，并在老年动物的循环中的激动剂的存在下，可能会提供一个分子的理解与年龄有关的变化，促进静脉血栓形成。 血小板储存有编码组织因子和其他相关蛋白质的RNA，适当的刺激引起活化依赖性剪接和翻译，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，沿着磷脂酰丝氨酸表达和微粒脱落。线粒体功能障碍解释了后一个过程。 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的多不饱和脂肪酸。一些磷脂氧化产物在结构上类似于PAF，并有效地激活先天免疫系统的所有细胞。其他被转运到细胞中并使线粒体脱蛋白，启动半胱天冬酶依赖性细胞凋亡，并允许磷脂酰丝氨酸展示在细胞表面上。这些激动剂是有效的，并且它们的形成不受调节。白藜芦醇是一种抗氧化剂，可以额外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了氧化磷脂，它们是PAF受体激动剂和有效地使线粒体去氧化的磷脂。这些水平的竞争对手的慢性炎症。我们 建议描述这些药物，并在4个目标中操纵它们的水平：定义年龄和性别相关的循环血栓形成/去极化介质的积累;分子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形成信号转导事件;确定白藜芦醇干预是否抑制年龄相关的静脉血栓形成。

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.