Dll4 in macrophage activation

描述（由申请人提供）：该多学科研究项目将测试Dll 4触发信号有助于动脉粥样硬化发病机制的新假设。我们将重点关注巨噬细胞源性蛋白水解活性，这是与急性冠状动脉事件发生相关的动脉重塑的典型特征。我们先前报道了Dll 4（Notch信号传导的配体）促进促炎因子（例如，iNOS，NF-：B）。Notch信号传导的作用是严格的细胞类型和环境依赖性的，并且Notch途径在巨噬细胞中的体内功能仍然未知。利用小鼠模型，本研究将探讨Dll 4-Notch轴在斑块巨噬细胞活化和动脉粥样硬化发展中的作用。具体目标1将检查Dll 4抗体施用是否减弱Ldlr-/-小鼠中的巨噬细胞活化和动脉粥样硬化形成。我们还将使用巨噬细胞靶向的Dll 4 siRNA的体内递送来确定巨噬细胞Dll 4的相对贡献。具体目标2将根据我们的数据说明Notch 3的促动脉粥样硬化作用。在Notch 3转基因小鼠和无效小鼠中测试该Notch受体促进巨噬细胞活化和动脉粥样硬化的假设。这些补充研究将提供巨噬细胞活化和动脉粥样硬化的新机制，并且还将提供Dll 4-Notch 3途径可以成为动脉粥样硬化、其并发症和其他血管疾病的治疗靶点的概念证明。 公共卫生相关性：冠状动脉炎症引发动脉粥样硬化的急性并发症（例如，心脏病发作）。然而，动脉炎症的机制仍然不完全清楚。我们以前使用的细胞培养系统，Delta样4（Dll 4）触发炎症。本研究将通过小鼠实验来剖析炎症和动脉粥样硬化的新机制。这些潜在的结果将为血管疾病提供新的治疗靶点，并有助于预防心血管疾病。

DESCRIPTION (provided by applicant): This multidisciplinary research project will test the novel hypothesis that Dll4-triggered signaling contributes to the pathogenesis of atherosclerosis. We will focus on macrophage-derived proteolytic activity, the key feature typical of arterial remodeling associated with the onset of acute coronary events. We previously reported that Dll4 (a ligand of Notch signaling) promotes expression or activation of pro-inflammatory factors (e.g., iNOS, NF-:B) in cultured macrophages. The role of Notch signaling is strictly cell-type- and context-dependent, and in vivo functions of the Notch pathway in macrophages remain unknown. Using mouse models, the present study will explore the role of the Dll4-Notch axis in activation of plaque macrophages and development of atherosclerosis. Specific Aim 1 will examine whether Dll4 antibody administration attenuates macrophage activation and atherogenesis in Ldlr-/- mice. We will also use macrophage-targeted in vivo delivery of Dll4 siRNA to determine the relative contribution of macrophage Dll4. Specific Aim 2 will address the role of Notch3 based on our data that suggested its pro-atherogenic role. In Notch3-transgenic and null mice to test the hypothesis that this Notch receptor promotes macrophage activation and athrogenesis. These complementary studies will offer novel mechanisms of macrophage activation and atherosclerosis, and will also provide proof of concept that the Dll4-Notch3 pathway can be a therapeutic target for atherosclerosis, its complications, and other vascular diseases. PUBLIC HEALTH RELEVANCE: Inflammation in coronary arteries triggers acute complications of atherosclerosis (e.g., heart attack). However, the mechanism for arterial inflammation remains incompletely understood. We previously used cell culture systems that Delta-like 4 (Dll4) triggers inflammation. The present study will perform mouse experiments to dissect the new mechanisms of inflammation and atherosclerosis. The potential outcomes will offer new therapeutic targets for vascular diseases and contribute to preventive cardiovascular medicine.