Viral Pathogenesis and Atherosclerosis

病毒发病机制和动脉粥样硬化

基本信息

批准号：
8769089
负责人：
DEBORAH Hye SPECTOR
金额：
$ 23.25万
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：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8769089
关键词：
Adherence Adhesions Affect Angioplasty Antigens Arterial Fatty Streak Arteries Atherosclerosis Binding Blood flow CD4 Positive T Lymphocytes CD8B1 gene Cardiovascular Diseases Cell physiology Cells Chronic Coculture Techniques Cytomegalovirus Cytomegalovirus Infections Development Disease Disease Progression Distal Endothelial Cells Environment Event Foundations Fractalkine Frequencies Functional disorder Gene Expression Generations Genes Goals Health Care Costs Homing Immune response Immune system Immunologics Immunology Individual Infection Infiltration Inflammation Inflammatory Interferons Lead Lesion Leukocytes Link Lymphocyte Maintenance Membrane Molecular and Cellular Biology Pathogenesis Peripheral Blood Mononuclear Cell Permeability Physiological Play Positioning Attribute Process Proteins Research Personnel Risk Risk Factors Role Signal Transduction Site Solid System T cell response T-Lymphocyte TNF gene Testing Trees Up-Regulation Vascular Diseases Viral Viral Antigens Viral Pathogenesis Virus Work atheroprotective cell injury chemokine cytokine design experience fluid flow fractalkine receptor hemodynamics insight interest macrophage monocyte monolayer novel novel strategies paracrine pathogen prevent public health relevance response restenosis shear stress translational medicine

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the major cause of cardiovascular disease. It is recognized as an inflammatory disorder involving endothelial cell (EC) dysfunction and infiltration of macrophages and lymphocytes into the arterial wall, but the events contributing to the chronic inflammation remain elusive. 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 ECs to protect against atherosclerosis and inflammation and that disturbed flow and low shear stress upregulates proatherosclerotic and proinflammatory 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? We hypothesize that infection of ECs and generation of a specific T cell response may be key factors. The significance of this proposal is that we will use a novel multifaceted approach to study interactions among HCMV, ECs, and PBMCs under conditions of flow and shear stress that closely mirror the conditions found in arteries susceptible to atherosclerosis. I brings together the extensive expertise in the Deborah Spector lab on molecular and cellular biology of HCMV and the broad experience in the Stephen Spector lab on HCMV pathogenesis, immunology, and translational medicine to test our hypothesis and assess the potential role of HCMV in atherosclerosis. Two specific aims are proposed: In Aim 1, we will determine how HCMV infection of aortic ECs impacts on expression of adhesion factors and inflammatory cytokines and chemokines under high vs. low shear stress. In Aim 2, we will determine how HCMV infection of aortic ECs and differential adhesion of HCMV immunologically primed and naive PBMCs under different flow conditions contribute to EC dysfunction. 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）：动脉粥样硬化是心血管疾病的主要原因。它被认为是一种涉及内皮细胞（EC）功能障碍以及巨噬细胞和淋巴细胞浸润到动脉壁的炎症疾病，但导致慢性炎症的事件仍然难以捉摸。动脉粥样硬化优先在动脉树的区域发展，其分支和曲率受到干扰，而剪切应力较低且不均匀。有越来越多的证据表明，具有高剪切应力的层流流量调节EC中的基因表达，以防止动脉粥样硬化和炎症，并且干扰流动和低剪切应力会上调促肌动蛋白膜性和促炎基因。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？我们假设EC的感染和特定T细胞反应的产生可能是关键因素。该提案的意义在于，我们将使用一种新型的多方面方法来研究HCMV，ECS和PBMC在流动和剪切应力条件下，这些方法与动脉粥样硬化易感的动脉中发现的条件紧密反映了这种情况。 I汇集了有关HCMV分子和细胞生物学的Deborah Spector Lab的广泛专业知识，以及在Stephen Spector Lab中有关HCMV发病机理，免疫学和转化医学的广泛经验，以测试我们的假设并评估HCMV在动脉粥样硬化中的潜在作用。提出了两个具体的目的：在AIM 1中，我们将确定主动脉EC的HCMV感染如何影响在高剪切应力与低剪切应力下的粘附因子和炎症细胞因子和趋化因子的表达。在AIM 2中，我们将确定HCMV感染主动脉EC的感染以及在不同流动条件下的HCMV免疫启动和幼稚PBMC的差异粘附有助于EC功能障碍。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。