Viral Pathogenesis and Atherosclerosis

病毒发病机制和动脉粥样硬化

• 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
• 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

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）功能障碍和巨噬细胞和淋巴细胞浸润到动脉壁中，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，其中血流受到干扰并且剪切应力低且不均匀。有越来越多的证据表明，层流高切应力调节基因表达的EC，以防止动脉粥样硬化和炎症和干扰流和低切应力上调促动脉粥样硬化和促炎基因。人巨细胞病毒（human cytomegalovirus，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？我们推测内皮细胞的感染和特异性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标：在目标1中，我们将确定HCMV感染的主动脉内皮细胞的粘附因子和炎症细胞因子和趋化因子的表达的影响，在高与低剪切应力。在目标2中，我们将确定HCMV感染的主动脉内皮细胞和HCMV免疫致敏和幼稚PBMC在不同的流动条件下的差异粘附如何导致EC功能障碍。这项提案的长期目标是提供新的见解动脉粥样硬化的发病机制。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。