Circulating Age-related Lipid Mediators in Thrombosis

血栓形成中循环年龄相关脂质介质

基本信息

批准号：
7896473
负责人：
Thomas M McIntyre
金额：
$ 53.3万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-20 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7896473
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 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 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 acronyms age related aged cyclooxygenase 2 dietary supplements feeding improved in vivo kinase inhibitor lipid mediator male novel oxidation oxidized low density lipoprotein platelet activating factor receptor receptor response stem theories

项目摘要

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的风险增加有关，但我们不了解将衰老与病理血栓形成事件倾向不断增加的因素有关。衰老的氧化理论在描述器官功能中与年龄相关的降低方面具有坚决的支持。不太明显的是，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。最近对血小板在这些血栓中的作用，对新型血小板激活模式的最新理解以及激动剂在老年动物循环中的存在可能会提供对年龄相关变化的分子理解，从而促进静脉血栓形成。血小板存储了编码组织因子和其他相关蛋白质的RNA，并且适当的刺激会导致激活依赖性剪接和翻译，从而重新编程了血小板的表型。其结果之一是血小板上的强组织因子表达以及磷脂酰丝氨酸表达和微粒脱落。线粒体功能障碍解释了后一个过程。衰老与促氧化态有关，氧化自由基的主要靶标是在膜磷脂中酯化的多不饱和脂肪酸。一些磷脂氧化产物结构类似于PAF，并有效激活先天免疫系统的所有细胞。其他人被运输到细胞中并将线粒体去极化，启动caspase依赖性凋亡，并允许在细胞表面显示磷脂酰丝氨酸。这些激动剂是有效的，它们的形成不受管制。白藜芦醇是一种抗氧化剂，可另外保护线粒体并降低非典型血小板受体的信号传导。我们发现在老年动物的循环中，氧化磷脂是PAF受体激动剂，并且有力地将线粒体去极化的磷脂。慢性炎症的这些竞争水平。我们提议描述这些药物，并在4个目标中操纵其水平：定义与年龄和性别相关的循环血栓/去极化介体的积累；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脉性信号转导事件；确定白藜芦醇干预是否抑制与年龄相关的静脉血栓形成。