Regulation of oxidative stress and vascular remodeling by EBP50

慢性炎症和氧化应激是许多与年龄有关的疾病的特征，包括 心血管疾病。迫切需要建立增加的分子和细胞基础 以及导致血管疾病的持续炎症和氧化状态。我们最近已经证明， 支架蛋白Ezrin结合蛋白50(EBP50，也被称为NHERF1)是一种关键的调控蛋白 全身和血管炎症。对小鼠和细胞系统的研究表明，炎症刺激 促进巨噬细胞和血管平滑肌细胞(VSMC)表达EBP50，反之， EBP50增加了这些细胞的炎症反应。初步研究还表明，EBP50 增加血管中活性氧物种的生成并加强氧化应激。这些发现 提示EBP50在控制炎症和氧化中的新的和病理相关的作用 压力。我们假设EBP50促进慢性炎症和氧化状态，这有助于 动脉粥样硬化和血管疾病。我们设计了三个具体的目标来检验这一假说并阐明 EBP50这些新的作用背后的分子机制。在目标1中，分子机制是通过 EBP50对氧化应激的调节作用将被阐明。目标2将确定EBP50的作用 调节线粒体功能以及对炎症和氧化刺激的反应。《目标3》中的小鼠 模型将被用来确定EBP50对新生内膜形成的影响。这项研究计划采用了 确定EBP50调节炎症和氧化的新机制的互补方法 压力。长期目标是确定和开发新的药物干预途径，目的是 限制慢性炎症和氧化应激。

Chronic inflammation and oxidative stress are hallmarks of many age-related diseases, including cardiovascular disease. There is a critical need to establish the molecular and cellular basis for the increased and sustained inflammatory and oxidative status that leads to vascular disease. We have recently shown that the scaffolding protein Ezrin Binding Protein 50 (EBP50, also known as NHERF1) is a key regulator of systemic and vascular inflammation. Studies in mice and in cell systems show that inflammatory stimuli promote EBP50 expression in macrophages and vascular smooth muscle cells (VSMC) and, conversely, EBP50 increases inflammatory responses in these cells. Preliminary studies also indicate that EBP50 increases the generation of reactive oxygen species and potentiates oxidative stress in vessels. These findings suggest a novel and pathologically relevant role for EBP50 in the control of both inflammation and oxidative stress. We hypothesize that EBP50 promotes a chronic inflammatory and oxidative status that contributes to atherosclerosis and vascular disease. Three specific aims are designed to test this hypothesis and elucidate the molecular mechanisms underlying these novel actions of EBP50. In Aim 1 that molecular mechanisms by which EBP50 regulates oxidative stress will be elucidated. Aim 2 will determine the actions of EBP50 that regulate mitochondrial function and the responses to inflammatory and oxidative stimuli. In Aim 3, murine models will be used to determine the effect of EBP50 on neointima formation. This research plan employs complementary methods to define a novel mechanism by which EBP50 regulates inflammation and oxidative stress. The long-term goal is to identify and exploit novel avenues for pharmacological intervention aimed at limiting chronic inflammation and oxidative stress.