Biologic Role of Cytomegalovirus in Endothelial Cell Inflammation and Atheroscler

巨细胞病毒在内皮细胞炎症和动脉粥样硬化中的生物学作用

基本信息

批准号：
8895567
负责人：
DEBORAH Hye SPECTOR
金额：
$ 54.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895567
关键词：
Address Adhesions Affect Angioplasty Animal Model Antigens Apolipoprotein E Area Arterial Fatty Streak Atherosclerosis Blood Vessels Blood flow CD8B1 gene Cardiovascular Diseases Cell Culture Techniques Cell physiology Cells Chronic Coagulation Process Cytomegalovirus Cytomegalovirus Infections Developed Countries Development Disease Disease Progression Distal Endothelial Cells Environment Event Gene Expression Genes Goals Health Health Care Costs Immune response Immunologics In Vitro Individual Infection Infiltration Inflammation Inflammatory Interferons Knowledge Lead Lesion Leukocytes Lymphocyte Maintenance Modeling Molecular Biology Molecular and Cellular Biology Mus Pathogenesis Physiological Play Positioning Attribute Prevention Process Relative (related person)Research Research Personnel Risk Factors Role Site Smooth Muscle Myocytes T-Lymphocyte Technical Expertise Testing Time Trees Vascular Diseases Viral Viral Antigens Virus atheroprotective cell injury cell motility chemokine cofactor cost effective cytokine design effective intervention experience fluid flow hemodynamics human subject in vivo in vivo Model insight interdisciplinary approach macrophage migration monocyte mortality mouse model novel novel strategies pathogen prevent response restenosis shear stress translational medicine viral DNA

项目摘要

DESCRIPTION (provided by applicant): The significance of this proposal is that it focuses on cardiovascular diseases which represent a leading cause of mortality in industrialized nations. Atherosclerosis preferentially develops in regions of the arterial tree with branches and curvatures where blood flow is disturbed and shear stress is low and non- uniform. There is increasing evidence that laminar blood flow with high shear stress modulates gene expression in endothelial cells (ECs) to protect against atherosclerosis, inflammation and coagulation, and that disturbed flow upregulates proatherosclerotic, proinflammatory, and procoagulant genes. It has long been suspected that human cytomegalovirus (HCMV) infection is a risk factor for vascular disease such as atherosclerosis and restenosis following angioplasty. The key question is what is the mechanism underlying HCMV's role in the disease process? Many studies have shown that HCMV infection induces proatherogenic gene expression in ECs, smooth muscle cells and monocytes/macrophages, but all these studies were performed in static cell culture, where there is no flow or shear stress. The Deborah Spector lab is the first t study HCMV infection of aortic ECs exposed to varying conditions of flow and shear stress. We hypothesize that flow conditions affect HCMV interaction with ECs and that this in turn modulates the EC functions and interactions with leukocytes, and smooth muscle cells to lead to lesion formation. Detailed knowledge of HCMV pathogenesis as well as in vivo animal models are required in order to address questions regarding the HCMV infection in EC inflammation. The novelty of this proposal is that it addresses the roles of HCMV infection and flow dyamics in atherosclerosis by an interdisciplinary approach. It brings together the extensive expertise in the Deborah Spector lab on molecular and cellular biology of HCMV and MCMV, the broad experience in the Stephen Spector lab on HCMV pathogenesis and translational medicine, and the vast knowledge and technical expertise of Joseph Witztum on the in vivo pathogenesis of atherosclerosis to test our hypothesis and assess the potential role of HCMV in atherosclerosis. Three Specific Aims are proposed. In Aim 1, we will determine the bi-directional interactions between HCMV and ECs under high vs. low shear stress (HSS vs. LSS). In Aim 2, we will determine the effect of HCMV infection of ECs on adhesion and transendothelial migration of Immunologically primed and na�ve PBMCs under conditions of HSS and LSS. In Aim 3, we will utilize in vivo studies to define the impact of MCMV on the ApoE-/- mouse model of atherosclerosis. The long- term objective of this proposal is to provide novel insights into the pathogenesis of atherosclerosis. Accomplishment of this goal will facilitate the development of new strategies designed to prevent and treat atherosclerotic disease.

描述（由申请人提供）：该提案的重要性在于它关注心血管疾病，心血管疾病是工业化国家死亡的主要原因，动脉粥样硬化优先发生在血流受到干扰和剪切的动脉树的分支和弯曲区域。越来越多的证据表明，高剪切应力的层流血流可调节内皮细胞 (EC) 的基因表达，从而预防动脉粥样硬化。长期以来，人们一直怀疑人类巨细胞病毒 (HCMV) 感染是动脉粥样硬化和血管成形术后再狭窄等血管疾病的危险因素。 HCMV在疾病过程中的作用机制是什么？许多研究表明，HCMV感染会诱导ECs中促动脉粥样硬化基因的表达，从而平滑肌细胞Deborah Spector 实验室首次研究了暴露于不同流动和剪切应力条件下的主动脉内皮细胞的 HCMV 感染。我们研究了流动条件影响 HCMV 与 EC 的相互作用，进而调节 EC 的功能以及与白细胞和平滑肌细胞的相互作用，从而导致病变形成。为了解决有关 EC 炎症中 HCMV 感染的问题，需要 HCMV 发病机制和体内动物模型。该提案的新颖之处在于它通过跨学科的方法共同探讨了 HCMV 感染和血流动力学在动脉粥样硬化中的作用。广泛的专业知识 Deborah Spector 实验室在 HCMV 和 MCMV 的分子和细胞生物学方面，Stephen Spector 实验室在 HCMV 发病机制和转化医学方面的丰富经验，以及 Joseph Witztum 在动脉粥样硬化体内发病机制方面的丰富知识和技术专长，以检验我们的假设和评估 HCMV 在动脉粥样硬化中的潜在作用提出了三个具体目标在目标 1 中，我们将确定高浓度下 HCMV 和 EC 之间的双向相互作用。在目标 2 中，我们将确定在 HSS 和 LSS 条件下，EC 的 HCMV 感染对免疫引发的原始 PBMC 的粘附和跨内皮迁移的影响。我们将利用体内研究来确定 MCMV 对 ApoE-/- 小鼠动脉粥样硬化模型的影响。为动脉粥样硬化的发病机制提供新的见解，这一目标的实现将有助于开发旨在预防和治疗动脉粥样硬化疾病的新策略。