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Atherosclerosis: Cytomegalovirus, Shear Stress, and Endothelial Cells

动脉粥样硬化：巨细胞病毒、剪切应力和内皮细胞

基本信息

批准号：
8269800
负责人：
DEBORAH Hye SPECTOR
金额：
$ 18.44万
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：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269800
关键词：
Address Affect Anatomy Aorta Area Arteries Atherosclerosis Blood Vessels Blood flow Brain Cardiovascular Diseases Cell Culture Techniques Cell Proliferation Cell physiology Cells Coagulation Process Coculture Techniques Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections Data Developed Countries Development Disease Disease Progression Endothelial Cells Endothelium Environment Event Gene Expression Genes Goals Health Care Costs Individual Infection Inflammation Lesion Leukocytes Location Microbe Molecular and Cellular Biology Pathogenesis Pattern Physiological Process Risk Factors Role Sclerosis Smooth Muscle Myocytes Source System Testing Time Transplantation Trees Umbilical vein Vascular Diseases Viral Virus Virus Diseases atherogenesis atheroprotective base cell injury cell type cost effective design effective intervention hemodynamics in vivo injured insight macrophage monocyte mortality novel novel strategies pathogen prevent regional difference restenosis shear stress

项目摘要

DESCRIPTION (provided by applicant): The significance of this proposal is that it focuses on cardiovascular diseases, a leading cause of mortality in industrialized nations. 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 endothelial cells to protect against atherosclerosis, inflammation and coagulation, and that disturbed flow upregulates proatherosclerotic, proinflammatory, and procoagulant genes. It has long been suspected that human cytomegalovirus (HCMV) infection is a risk factor for vascular disease such as atherosclerosis, arterial restenosis, and transplant vascular sclerosis. The key question is what is the mechanism underlying HCMV's role in atherogenesis? Many studies have shown that HCMV infection induces proatherogenic gene expression in endothelial cels, but these studies were all performed in static cell culture, where there is no flow or shear stress. Likewise, the role of differential blood flow patterns on endothelial cell function has never been studied in the context of HCMV infection. In addition, the use of different types of endothelial cells (macrovascular vs. microvascular) from different anatomic locations (umbilical vein, brain, aorta) both for HCMV infection and shear stress studies makes comparison of data very difficult. We hypothesize that flow conditions affect HCMV interaction specifically with aortic endothelial cells and that this in turn modulates endothelial cell function. The novelty of this proposal is that it addresses the roles of HCMV infection and flow dynamics in atherogenesis by a multifaceted approach. The major aim is to determine the bi-directional interactions between HCMV and aortic endothelial cells under high vs. low shear stress and answer the following questions: 1) How does shear stress affect the progression of HCMV infection in the endothelial cells? And 2) How does HCMV affect proatherogenic and prothrombotic gene expression in the aortic endothelial cells under different patterns of flow and shear stress? The 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）：该提案的重要性在于它重点关注心血管疾病，心血管疾病是工业化国家死亡的主要原因。动脉粥样硬化优先发生在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，具有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、炎症和凝血，并且受干扰的血流上调促动脉粥样硬化、促炎和促凝血基因。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、动脉再狭窄和移植血管硬化等血管疾病的危险因素。关键问题是 HCMV 在动脉粥样硬化形成中发挥作用的机制是什么？许多研究表明，HCMV 感染会诱导内皮细胞中促动脉粥样硬化基因表达，但这些研究都是在静态细胞培养中进行的，其中没有流动或剪切应力。同样，在 HCMV 感染的情况下，差异血流模式对内皮细胞功能的作用也从未被研究过。此外，使用来自不同解剖位置（脐静脉、大脑、主动脉）的不同类型的内皮细胞（大血管与微血管）进行 HCMV 感染和剪切应力研究使得数据比较变得非常困难。我们假设血流条件影响 HCMV 特别与主动脉内皮细胞的相互作用，并且这反过来又调节内皮细胞功能。该提案的新颖之处在于它通过多方面的方法解决了 HCMV 感染和血流动力学在动脉粥样硬化形成中的作用。主要目的是确定高剪切应力和低剪切应力下 HCMV 和主动脉内皮细胞之间的双向相互作用，并回答以下问题：1）剪切应力如何影响内皮细胞中 HCMV 感染的进展？ 2）在不同的流动和剪切应力模式下，HCMV 如何影响主动脉内皮细胞中促动脉粥样硬化和促血栓基因的表达？该提案的目的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。