Dll4 in macrophage activation

巨噬细胞激活中的 Dll4

基本信息

批准号：
8403768
负责人：
Masanori Aikawa
金额：
$ 51.09万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8403768
关键词：
Acute Address Adult Animals Antibodies Arterial Fatty Streak Atherosclerosis Attenuated Binding Biological Response Modifier Therapy Blocking Antibodies Cardiovascular system Cell Culture System Cell Nucleus Cells Cholesterol Clinical Collagen Coronary Coronary artery Data Development Disease Encapsulated Event Future Genes Genetic Transcription Goals Homeostasis Immune system In Vitro Inflammation Inflammatory Integral Membrane Protein Interdisciplinary Study Knockout Mice Lead Ligands Link Lipids Low Density Lipoprotein Receptor Macrophage Activation Medicine Modeling Mouse Strains Mus Myocardial Infarction Outcome Pathogenesis Pathway interactions Patients Phenotype Pilot Projects Play Preventive Process Proteins Relative (related person)Reporting Research Project Grants Role Signal Transduction Small Interfering RNA Testing Thrombosis Tissues Transgenic Mice Translations United States Vascular Diseases arterial remodeling atherogenesis base cell type collagenase feeding gain of function in vivo insight loss of function macrophage mouse model nanoparticle new therapeutic target notch protein novel novel therapeutics overexpression pre-clinical promoter receptor research study therapeutic target

项目摘要

Project Summary 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.

项目概要这个多学科研究项目将测试 Dll4 触发信号传导的新假设我们将重点关注巨噬细胞衍生的蛋白水解活性，这是动脉粥样硬化的发病机制的关键。与急性冠状动脉事件发生相关的典型动脉重塑特征。报道称 Dll4（Notch 信号传导的配体）促进促炎因子的表达或激活（例如，iNOS、NF-¿B）在培养的巨噬细胞中 Notch 信号传导的作用严格取决于细胞类型和环境。 Notch 通路在巨噬细胞中的依赖性和体内功能仍然未知。模型中，本研究将探讨 Dll4-Notch 轴在斑块巨噬细胞激活中的作用具体目标 1 将检查是否施用 Dll4 抗体。减弱 Ldlr-/- 小鼠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。体内递送 Dll4 siRNA 以确定巨噬细胞 Dll4 的相对贡献具体目标 2 将。根据我们的数据说明了 Notch3 在 Notch3 转基因中的促动脉粥样硬化作用。和无效小鼠来测试该 Notch 受体促进巨噬细胞活化的假设这些补充研究将提供巨噬细胞激活和关节炎发生的新机制。动脉粥样硬化，并且还将提供 Dll4-Notch3 通路可以作为治疗药物的概念证明动脉粥样硬化及其并发症和其他血管疾病的目标。