Dedicator of cytokinesis 2 in atherosclerosis

动脉粥样硬化中胞质分裂2的奉献者

基本信息

批准号：
10166613
负责人：
XIA GUO
金额：
$ 24.9万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10166613
关键词：
Adhesions Adipose tissue Arterial Fatty Streak Atherosclerosis Attenuated CCL2 gene CD36 gene Cause of Death Cell Adhesion Cell Adhesion Molecules Cells Cessation of life Chronic Complex Coronary Arteriosclerosis Cytokinesis Data Development Diet Disease Endothelial Cells Endothelium Event Foam Cells Functional disorder Genes Hematopoietic Human Infiltration Inflammation Inflammatory Inflammatory Response Intercellular adhesion molecule 1 Interleukin-6 Knockout Mice Lead Lesion Lipids Low-Density Lipoproteins Lymphocyte Macrophage Activation Mediating Mediator of activation protein Metabolic Diseases Molecular Mus Myocardial Infarction Oxides Pathogenesis Patients Peripheral arterial disease Phagocytosis Pharmaceutical Preparations Phase Phenotype Physiological Play Process Production Reporting Risk Factors Role Signal Pathway Stroke TNF gene Testing Therapeutic Therapeutic Agents United States Vascular Cell Adhesion Molecule-1 Vascular Endothelial Cell Vascular remodeling atherogenesis cadherin 5 cytokine in vivo macrophage migration monocyte mouse model novel novel therapeutics oxidized low density lipoprotein promoter scavenger receptor uptake vascular inflammation

项目摘要

Atherosclerosis, the major common risk factor of coronary artery disease and stroke, is the primary cause of death particularly in the developed world. The pathophysiological mechanisms of atherosclerosis are quite complex, and the inflammatory responses of vascular endothelial cells (ECs), the adhesion and infiltration of monocytes, and the oxidized LDL (ox-LDL)-induced transformation of macrophages (Mϕ) into foam cells are vital events in this process. However, molecular mechanisms underlying the EC inflammation, the monocyte adhesion to ECs, and the activation/function of Mϕ especially factors regulating these processes in atherosclerosis remain largely unknown. Our exciting preliminary data strongly support that dedicator of cytokinesis 2 (DOCK2) is a novel regulator for EC inflammation, monocyte adhesion, and Mϕ activation/function in atherogenesis. DOCK2 is essential for ox-LDL- or TNF-α-induced expression of proinflammatory cytokines and adhesion molecules such as IL-6, MCP-1, ICAM-1, and VCAM-1 in ECs, suggesting that DOCK2 mediates EC inflammation. In addition, DOCK2 deficiency (DOCK2-/-) inhibits TNF-α- induced human monocyte adhesion to ECs and blocks Mϕ activation/function. Moreover, DOCK2-/- decreases macrophage phagocytosis through the suppression of scavenger receptor A (SR-A) and SR-B (CD36). In vivo, DOCK2 is induced in both mouse and human atherosclerotic lesion ECs and other cells. DOCK2-/- in mice significantly attenuates the lesion size, Mϕ infiltration, and the expression of adhesion molecules and proinflammatory cytokines including NF-κB, the most common regulator of inflammation in atherosclerosis. These findings strongly support a novel hypothesis that DOCK2 promotes the development of atherosclerosis through mediating EC inflammation, monocyte adhesion to ECs as well as Mϕ function, which will be tested by three Specific Aims. In Aim 1 we will establish the role of DOCK2 in atherosclerosis formation in vivo by examining the modulation of EC inflammation/phenotype. In Aim 2 we will test whether DOCK2 mediates monocyte adhesion to ECs by regulating endothelial inflammation and adhesion molecule expression; and in Aim 3 we will determine if DOCK2 regulates the development of atherosclerosis through mediating Mϕ activation/function. Completion of the proposed studies will establish the pivotal role of DOCK2 and the underlying novel mechanisms controlling the development and progression of atherosclerosis, which may ultimately contribute to the development of novel therapeutics for treating atherosclerosis.

动脉粥样硬化是冠状动脉疾病和中风的主要常见危险因素，是在发达国家特别是死亡。动脉粥样硬化的病理生理机制非常复合物以及血管内皮细胞（EC）的炎症反应，粘附和浸润单核细胞和氧化的LDL（OX-LDL）诱导的巨噬细胞转化（Mϕ）向泡沫细胞转化为在此过程中的重要事件。但是，EC炎症的基础机制，单核细胞对EC的粘附以及M ϕ的激活/功能尤其是控制这些过程的因素动脉粥样硬化仍然未知。我们令人兴奋的初步数据强烈支持细胞因子2（DOCK2）是EC炎症，单核细胞粘合剂和Mϕ的新型调节剂动脉粥样硬化中的激活/功能。 DOCK2对于OX-LDL-或TNF-α诱导的促炎性表达至关重要 ECS中的细胞因子和粘合分子，例如IL-6，MCP-1，ICAM-1和VCAM-1，表明Dock2介导了EC炎症。此外，dock2缺乏症（dock2 - / - ）抑制了TNF-α- 诱导人类的单核细胞粘附于EC并阻止M ϕ激活/功能。此外，dock2 - / - 下降通过抑制清道夫受体A（SR-A）和SR-B（CD36），巨噬细胞吞噬作用。体内，小鼠和人动脉粥样硬化病变EC和其他细胞都诱导了DOCK2。 dock2 - / - 在小鼠中显着减轻了病变的大小，M ϕ浸润以及粘合分子和促炎的表达包括NF-κB在内的细胞因子，NF-κB是动脉粥样硬化中最常见的炎症调节剂。这些发现强烈支持了一个新的假设，即Dock2促进了动脉粥样硬化的发展通过介导EC炎症，对EC的单核细胞粘附以及Mϕ功能，将通过三个具体目标。在AIM 1中，我们将确定Dock2在体内动脉粥样硬化形成中的作用检查EC炎症/表型的调节。在AIM 2中，我们将测试Dock2是否介导通过调节内皮注射和粘合分子的表达，单核细胞粘附于EC；并在 AIM 3我们将确定Dock2是否通过介导M ϕ调节动脉粥样硬化的发展激活/功能。拟议研究的完成将确定Dock2和控制动脉粥样硬化的发展和发展的基本新机制，这可能最终有助于开发用于治疗动脉粥样硬化的新疗法。