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（由适用提供）：该提案的重要性是它的重点是心血管疾病，这代表了工业化国家死亡的主要原因。动脉粥样硬化优先在艺术树的区域发展，其分支和曲率受到干扰，而剪切应力则低且不均匀。越来越多的证据表明，具有高剪切应力的层流流量调节内皮细胞（ECS）中的基因表达，以防止动脉粥样硬化，感染和凝结，并且影响流动的流动上调了促进性促进性，促炎，促炎和促凝基因。长期以来一直怀疑人类巨细胞病毒（HCMV）感染是血管性血管成形术后动脉粥样硬化和再狭窄等血管疾病的危险因素。关键问题是HCMV在疾病过程中的作用是什么？许多研究表明，HCMV感染在EC，平滑肌细胞和单核细胞/巨噬细胞中诱导了促进性基因表达，但是所有这些研究都是在没有流动或剪切应力的静态细胞培养中进行的。 Deborah Spector Lab是第一个研究的HCMV感染，该研究暴露于流动和剪切应力的不同条件下。我们假设流动条件会影响HCMV与EC的相互作用，这反过来又调节了EC功能和与白细胞的相互作用，而平滑肌细胞则导致病变形成。为了解决有关EC感染中HCMV感染的问题，需要对HCMV发病机理以及体内动物模型的详细知识。该提议的新颖性是，它通过跨学科方法解决了HCMV感染和流节律在动脉粥样硬化中的作用。它汇集了广泛的专业知识 Deborah Spector实验室关于HCMV和MCMV的分子和细胞生物学，在Stephen Spector实验室的HCMV发病机理和转化医学方面的广泛经验，以及Joseph Witztum在体内对动脉粥样硬化的体内病理的知识和技术专业知识，以测试我们的动脉粥样硬化和评估HCMV的潜在作用。提出了三个具体目标。在AIM 1中，我们将在高剪切应力（HSS与LSS）下确定HCMV与EC之间的双向相互作用。在AIM 2中，我们将在HSS和LSS的条件下确定EC感染HCMV感染对免疫学启动和unave PBMC的广告和跨性皮迁移的影响。在AIM 3中，我们将利用体内研究来定义MCMV对动脉粥样硬化的APOE - / - 小鼠模型的影响。该提案的长期目标是提供有关动脉粥样硬化发病机理的新见解。实现这一目标将有助于制定旨在预防和治疗动脉粥样硬化疾病的新策略。