Alcohol-LPP3 axis in ischemic stroke

项目摘要 酗酒的并发症，如中风和心肌病是成年人死亡的主要原因。的 这些事件的潜在病理生理学涉及易感动脉内的脂质，导致随后的 局部炎症和血管功能障碍。而生物活性甘油磷脂溶血磷脂酸 在动脉粥样硬化疾病中起着众所周知的作用，它在酒精介导的脑功能障碍中的作用仍然存在 几乎未被探索过溶血磷脂酸的产生涉及溶血磷脂酰胆碱被磷脂酰胆碱水解。 分泌的酶autotaxin，而脂质磷酸磷酸酶-3（LPP 3）催化溶血磷脂酸 去磷酸化以产生非受体活性的脂质产物。在本申请中，我们提出了第一个 有证据表明，大量饮酒（HAC）可增强脑血管自分泌运动因子水平， LPP 3表达，这与溶血磷脂酸信号传导增加有关。HAC时，无反应 氧自由基（ROS）在血管中增加，而氧化还原敏感性转录因子 NFAT（活化的T细胞的核因子）已被证明与自分泌运动因子启动子结合并诱导其表达。 表情类似地，在HAC的情况下，氧化应激可通过降低LPP 3水平来消耗LPP 3水平。 表达或增强的LPP 3降解。因此，我们假设HAC改变了自分泌运动因子和LPP 3， 通过ROS产生来驱动溶血磷脂酸信号传导和脑血管功能障碍。 以下相互关联的具体目标旨在提供体外、体内、 和实验治疗环境中。具体目标1将评估ROS产生在自运动因子中的作用。 表达和溶血磷脂酸的产生。具体目标2将 确定ROS产生在LPP 3消耗和LPA产生中的作用， HAC。我们可以确定细胞与线粒体抗氧化状态的调节是否赋予了一个 HAC后的差动保护作用。我们的结果应该提供具体的洞察信号系统 可能为治疗提供新的靶点，并可能改善脑血管疾病。

Project Abstract Complications of alcoholism such as stroke and cardiomyopathy are leading causes of death among adults. The underlying pathophysiology of these events involves lipids within susceptible arteries leading to subsequent localized inflammation and vascular dysfunction. While the bioactive glycerophospholipid lysophosphatidic acid plays a well-known role in atherosclerotic disease, its role in alcohol-mediated cerebral dysfunction remains virtually unexplored. Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes lysophosphatidic acid dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that heavy alcohol consumption (HAC) enhances the cerebrovascular autotaxin levels and decreases LPP3 expression, and this is associated with increased lysophosphatidic acid signaling. Upon HAC, reactive oxygen species (ROS) increases in the cerebrovasculature, whereas the redox-sensitive transcription factor NFAT (a nuclear factor of activated T-cells) has been shown to bind to the autotaxin promoter and induce its expression. Similarly, oxidant stress may deplete LPP3 levels in the context of HAC through reduced LPP3 expression or enhanced LPP3 degradation. Thus, we hypothesize that HAC alters autotaxin and LPP3 expression through ROS production to drive lysophosphatidic acid signaling and cerebrovascular dysfunction. The following interrelated specific aims are designed to provide step-wise and in-depth studies in vitro, in vivo, and in experimental therapeutics settings. Specific aim 1 will assess the role of ROS production in autotaxin expression and lysophosphatidic acid production in the cerebrovasculature following HAC. Specific aim 2 will determine the role of ROS production in LPP3 depletion and LPA production in the cerebrovasculature following HAC. We could identify whether modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect following HAC. Our results should provide specific insight into signaling systems mediated by HAC and may provide novel targets for treatment and might improve cerebrovascular disorders.