Viral Pathogenesis and Atherosclerosis

描述（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）功能障碍和巨噬细胞和淋巴细胞浸润到动脉壁，但导致慢性炎症的事件尚不清楚。动脉粥样硬化优先发生在动脉树中有分支和弯曲的区域，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，高剪切应力下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，而血流紊乱和低剪切应力上调促动脉粥样硬化和促炎症基因。长期以来，人们一直怀疑人类巨细胞病毒（HCMV）感染是血管疾病（如动脉粥样硬化和血管成形术后再狭窄）的危险因素。关键问题是HCMV在疾病过程中的作用机制是什么？我们假设ECs的感染和特定T细胞反应的产生可能是关键因素。这项提议的意义在于，我们将使用一种新的多方面的方法来研究HCMV、ECs和PBMCs在流动和剪切应力条件下的相互作用，这些条件与动脉粥样硬化易感动脉的条件密切相关。I汇集了Deborah Spector实验室在HCMV分子和细胞生物学方面的广泛专业知识，以及Stephen Spector实验室在HCMV发病机制、免疫学和转化医学方面的广泛经验，以验证我们的假设并评估HCMV在动脉粥样硬化中的潜在作用。在目的1中，我们将确定HCMV感染主动脉内皮细胞在高剪切应力和低剪切应力下对粘附因子、炎症细胞因子和趋化因子表达的影响。在Aim 2中，我们将确定HCMV感染主动脉内皮细胞以及不同血流条件下HCMV免疫启动和初始pbmc的差异粘附是如何导致内皮细胞功能障碍的。这项提议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发展。

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.