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。它被认为是一种炎症性疾病，涉及内皮细胞 (EC) 功能障碍以及巨噬细胞和淋巴细胞浸润动脉壁，但导致慢性炎症的事件仍然难以捉摸。动脉粥样硬化优先发生在具有分支和弯曲的动脉树区域，这些区域血流受到干扰，剪切应力低且不均匀。越来越多的证据表明，高剪切应力的层流血流调节内皮细胞中的基因表达，以防止动脉粥样硬化和炎症，并且血流紊乱和低剪切应力上调促动脉粥样硬化和促炎基因。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。关键问题是HCMV在疾病过程中发挥作用的机制是什么？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，我们将使用一种新颖的多方面方法来研究在流动和剪切应力条件下 HCMV、EC 和 PBMC 之间的相互作用，这些条件密切反映了易患动脉粥样硬化的动脉中发现的条件。我汇集了 Deborah Spector 实验室在 HCMV 分子和细胞生物学方面的丰富专业知识以及 Stephen Spector 实验室在 HCMV 发病机制、免疫学和转化医学方面的丰富经验，以检验我们的假设并评估 HCMV 在动脉粥样硬化中的潜在作用。提出了两个具体目标：在目标 1 中，我们将确定主动脉 EC 的 HCMV 感染如何在高剪切应力和低剪切应力下影响粘附因子、炎症细胞因子和趋化因子的表达。在目标 2 中，我们将确定主动脉 EC 的 HCMV 感染以及不同血流条件下 HCMV 免疫引发和初始 PBMC 的差异粘附如何导致 EC 功能障碍。该提案的长期目标是为动脉粥样硬化的发病机制提供新的见解。这一目标的实现将促进旨在预防和治疗动脉粥样硬化疾病的新策略的开发。