Vessel Shear Stress & Cytomegalovirus Disease: Molecular Basis of Atherosclerosis

容器剪应力

• 批准号: 8001590
• 负责人: Jenny B DuRose
• 金额: $ 4.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001590
• 关键词: Adhesions; Adult; Arterial Fatty Streak; Arteries; Atherosclerosis; Biological Models; Blood Vessels; Blood flow; Cardiovascular Diseases; Cell Communication; Cells; Cytomegalovirus; Cytomegalovirus Infections; Developed Countries; Development; Disease; Disease Progression; Endothelial Cells; Environment; Functional disorder; Gene Expression; Goals; Health Care Costs; Heart Diseases; Hereditary Disease; Human; Inflammatory; Leukocytes; Liquid substance; Pathogenesis; Pattern; Physiological; Population; Prevalence; Prevention strategy; Proteins; RNA; Research; Risk Factors; Role; Simulate; Stroke; System; Viral; Viral Pathogenesis; Virus; atherogenesis; base; cell injury; cell type; cost effective; disability; hemodynamics; insight; migration; mortality; novel; novel strategies; pathogen; peripheral blood; public health relevance; shear stress

DESCRIPTION (provided by applicant): Heart disease and stroke are the principal causes of mortality and long-term disability in developed nations. The major underlying cause of cardiovascular diseases is atherosclerosis, which is widely recognized as an inflammatory disease initiated by endothelial cell injury or dysfunction. Human cytomegalovirus (HCMV), a widely disseminated human pathogen, has long been proposed as a risk factor for cardiovascular disease. The pathogenesis of atherosclerosis involves interactions between multiple cell types and typically occurs in large to medium-sized arteries in regions that are branched or curved, which are exposed to disturbed patterns of blood flow and low fluid shear stress. To date, the role of HCMV infection in atherosclerosis has only been explored in static conditions. Given the importance cell-cell interactions and the role of blood flow in atherogenesis, the major goal of this research plan is to uncover key mechanisms in HCMV induced atherosclerosis in a physiological context using a flow model system. We plan to explore the bi-directional interactions of HCMV and endothelial cells under conditions of high or low shear stress in uniform and turbulent flow. To do this we will culture endothelial cells in chambers that will allow for the regulated flow of media over cells simulating blood flow. The use of uniform and step-flow chambers will allow us to simulate different types of flow patterns and shear stresses that occur in different parts of the vasculature. Using these systems we plan to analyze the effects of HCMV infection in endothelial cells exposed to varying flow patterns and shear stress as it relates to viral progression and proatherosclerotic gene expression at the protein and RNA level. In addition, we plan to determine how HCMV infection of endothelial cells in the context of flow ultimately modulates the adhesion and transendothelial migration of peripheral blood leukocytes, which is the major initial step in the development of atherosclerotic lesions. As a whole, this research plan is intended to explore the interactions between HCMV, endothelial cells, and leukocytes in the physiological context of blood flow in order to elucidate the mechanisms of HCMV induced atherosclerosis. Given the prevalence of HCMV in the human population (60-80% of adults), the mortality associated with atherosclerosis, and its impact on healthcare costs, there is a great need to determine the role of HCMV infection in the progression of atherogenesis in the physiological conditions that occur in the human artery. The long-term goal of this research plan is to provide novel insights into viral pathogenesis of atherosclerosis leading to cost effective new strategies for prevention of endothelial cell damage associated with HCMV infection. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the major cause cardiovascular diseases (the leading cause of mortality in developed countries) and its impact on health care costs is enormous. Hemodynamic factors are major regulators of atherosclerosis, and human cytomegalovirus (HCMV) infection has been proposed as an important factor in disease progression. The proposed project employs novel approaches to study the effects of HCMV infection on vascular functions in a dynamic flow environment, and the results will fill the current gap in our understanding of bi-directional interactions between virus and vascular cells in physiological or pathological environments, thus facilitating the discovery of new therapies.

描述（由申请人提供）：心脏病和中风是发达国家死亡和长期残疾的主要原因。心血管疾病的主要潜在原因是动脉粥样硬化，其被广泛认为是由内皮细胞损伤或功能障碍引起的炎性疾病。人巨细胞病毒（HCMV）是一种广泛传播的人类病原体，长期以来一直被认为是心血管疾病的危险因素。动脉粥样硬化的发病机制涉及多种细胞类型之间的相互作用，并且通常发生在分支或弯曲区域中的大到中等尺寸的动脉中，其暴露于血流的干扰模式和低流体剪切应力。迄今为止，HCMV感染在动脉粥样硬化中的作用仅在静态条件下进行了研究。鉴于细胞间相互作用的重要性和血流在动脉粥样硬化形成中的作用，本研究计划的主要目标是使用流动模型系统在生理背景下揭示HCMV诱导动脉粥样硬化的关键机制。我们计划探索在均匀和湍流的高或低剪切应力条件下HCMV和内皮细胞的双向相互作用。为了做到这一点，我们将在腔室中培养内皮细胞，这将允许培养基在模拟血流的细胞上的调节流动。使用均匀和阶跃流动腔室将允许我们模拟在脉管系统的不同部分中发生的不同类型的流动模式和剪切应力。使用这些系统，我们计划分析HCMV感染的内皮细胞暴露于不同的流动模式和剪切力的影响，因为它涉及到病毒的进展和前动脉粥样硬化的基因表达在蛋白质和RNA水平。此外，我们计划确定如何HCMV感染的内皮细胞在流动的背景下，最终调节外周血白细胞的粘附和跨内皮迁移，这是动脉粥样硬化病变发展的主要初始步骤。总体而言，本研究计划旨在探讨HCMV、内皮细胞和白细胞在血流生理背景下的相互作用，以阐明HCMV诱导动脉粥样硬化的机制。考虑到HCMV在人群中的流行率（60-80%的成人）、与动脉粥样硬化相关的死亡率及其对医疗费用的影响，非常需要确定HCMV感染在人体动脉中发生的生理条件下动脉粥样硬化形成进展中的作用。这项研究计划的长期目标是提供新的见解动脉粥样硬化的病毒发病机制，导致成本效益的新策略，预防与HCMV感染相关的内皮细胞损伤。 公共卫生相关性：动脉粥样硬化是心血管疾病（发达国家死亡率的主要原因）的主要原因，其对医疗保健费用的影响是巨大的。血流动力学因素是动脉粥样硬化的主要调节因子，人巨细胞病毒（HCMV）感染已被认为是疾病进展的重要因素。该项目采用新的方法来研究HCMV感染对动态流动环境中血管功能的影响，其结果将填补我们目前对生理或病理环境中病毒与血管细胞之间双向相互作用的理解空白，从而促进新疗法的发现。