Dll4 in macrophage activation

巨噬细胞激活中的 Dll4

基本信息

批准号：
8236700
负责人：
Masanori Aikawa
金额：
$ 55.7万
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/8236700
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

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.

描述（由申请人提供）：这个多学科研究项目将测试 Dll4 触发信号传导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衍生的蛋白水解活性，这是与急性冠状动脉事件发生相关的动脉重塑的典型关键特征。我们之前报道过 Dll4（Notch 信号传导的配体）可促进培养的巨噬细胞中促炎因子（例如 iNOS、NF-:B）的表达或激活。 Notch 信号传导的作用严格依赖于细胞类型和环境，并且 Notch 通路在巨噬细胞中的体内功能仍然未知。本研究将使用小鼠模型探讨 Dll4-Notch 轴在斑块巨噬细胞激活和动脉粥样硬化发展中的作用。具体目标 1 将检查 Dll4 抗体给药是否会减弱 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 Dll4 siRNA 体内靶向巨噬细胞的递送来确定巨噬细胞 Dll4 的相对贡献。具体目标 2 将根据我们表明其促动脉粥样硬化作用的数据来阐述 Notch3 的作用。在 Notch3 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激活和动脉粥样硬化的新机制，并且还将提供 Dll4-Notch3 通路可以成为动脉粥样硬化及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：冠状动脉炎症会引发动脉粥样硬化的急性并发症（例如心脏病发作）。然而，动脉炎症的机制仍不完全清楚。我们之前使用的细胞培养系统是 Delta-like 4 (Dll4) 触发炎症。本研究将进行小鼠实验来剖析炎症和动脉粥样硬化的新机制。潜在的结果将为血管疾病提供新的治疗靶点，并有助于预防性心血管医学。