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）：该提案的重要性是它专注于心血管疾病，这是工业化国家死亡率的主要原因。动脉粥样硬化优先在带有分支和曲率的动脉树的区域发展，其中血流受到干扰，剪切应力较低且不均匀。越来越多的证据表明，层状血流带有高剪切应力会调节内皮细胞中的基因表达，以防止动脉粥样硬化，炎症和凝结，并且干扰流动的流动上调了促进性骨膜硬化，促炎，促炎和突发凝基因。长期以来一直怀疑人类巨细胞病毒（HCMV）感染是血管疾病的危险因素，例如动脉粥样硬化，动脉再狭窄和移植血管硬化。关键问题是HCMV在动脉粥样硬化中的作用是什么？许多研究表明，HCMV感染在内皮碳中诱导了促进性基因的表达，但是这些研究均在没有流动或剪切应力的静态细胞培养中进行。同样，在HCMV感染的背景下，从未研究过差异血流模式对内皮细胞功能的作用。此外，从不同解剖位置（脐静脉，大脑，主动脉）中使用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，从而使数据的比较非常困难。我们假设流动条件会影响与主动脉内皮细胞的HCMV相互作用，并且这又调节了内皮细胞功能。该提案的新颖性是它通过多方面的方法解决了HCMV感染和动态动力学在动脉粥样硬化中的作用。主要目的是确定在高剪切应力和低剪切应力下HCMV与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）HCMV如何在不同的流动和剪切应力模式下影响主动脉内皮细胞中的促孕激素和血栓性基因表达？该提案的目的是提供有关动脉粥样硬化发病机理的新见解。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疾病的新策略。