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.

简介(申请人提供)：动脉粥样硬化是导致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渗入动脉壁，但导致慢性炎症的事件仍不清楚。动脉粥样硬化主要发生在动脉树有分支和弯曲的区域，这些区域的血液流动受到干扰，切应力低且不均匀。越来越多的证据表明，具有高切应力的层流血流调节内皮细胞的基因表达，以防止动脉粥样硬化和炎症，而扰动的血流和低切应力上调了促动脉粥样硬化和促炎基因。长期以来，人们一直怀疑人巨细胞病毒(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，巨细胞病毒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定T细胞反应的产生可能是关键因素。这一建议的意义在于，我们将使用一种新的多方面方法来研究流动和切应力条件下HCMV、ECs和PBMCs之间的相互作用，这些条件与动脉粥样硬化的易感条件密切相关。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，以验证我们的假设并评估HCMV在动脉粥样硬化中的潜在作用。目的1，研究高切应力与低切应力条件下人巨细胞病毒感染对血管内皮细胞黏附因子、炎性细胞因子和趋化因子表达的影响。在目的2中，我们将研究在不同的血流条件下，人巨细胞病毒感染的主动脉内皮细胞和免疫激活的和未接种的外周血单核细胞在不同的血流条件下对内皮细胞的不同黏附作用。这项建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。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性疾病的新战略。