P2: MOLECULAR MECHANISMS OF WEST NILE VIRUS NEUROINVASION

P2：西尼罗病毒神经侵袭的分子机制

• 批准号: 8360754
• 负责人: SAGUNA VERMA
• 金额: $ 21.89万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360754
• 关键词: Animal Model; Blood - brain barrier anatomy; Blood Cells; Brain; Brain Diseases; Cell Culture Techniques; Culicidae; Dinoprostone; Disease; Disease Outcome; Emerging Communicable Diseases; Enzymes; Funding; Grant; Human; In Vitro; Infectious Diseases Research; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Meningoencephalitis; Modeling; Molecular; National Center for Research Resources; Pathogenesis; Pharmaceutical Preparations; Principal Investigator; Production; Proteins; Research; Research Infrastructure; Resources; Role; Signal Pathway; Source; Therapeutic; Tight Junctions; United States National Institutes of Health; Vaccines; Virus Diseases; West Nile virus; brain cell; cost; cyclooxygenase 2; improved; insight; monocyte; mouse model; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. West Nile virus (WNV), which is transmitted by mosquitoes, usually causes a mild disease in humans. In approximately 2% of infected people, however, WNV causes a fatal brain disease, called meningoencephalitis. Currently, there are no drugs to treat WNV or vaccines to prevent WNV infection in humans. Our preliminary studies indicate that WNV gains entry into the brain by crossing the blood-brain barrier (BBB) and produces mediators, such as enzymatic proteins called matrix metalloproteinases (MMPs), that degrade the BBB. Our central hypothesis is that the increased production of MMPs by WNV-infected blood and brain cells, via the cyclooxygenase-2 (COX-2) signaling pathway, mediates BBB breakdown by degrading specific tight junction proteins (TJP). We will pursue three specific aims: Aim 1 will analyze the role of COX-2 enzyme and its product, Prostaglandin E2, in regulating the levels of MMPs. In Aim 2, we will assess the ability of WNV-infected monocytes to degrade TJP and its transmigration across a well-established in vitro BBB model. Aim 3 will employ a mouse model to characterize WNV-induced alterations in TJP. Further, we will also determine the potential of MMP inhibitors to prevent BBB disruption and eventual entry of WNV into the CNS. Our comprehensive study using cell culture and animal model will highlight the role of MMPs-induced BBB disruption in WNV disease pathogenesis. The discovery of new insights into the function(s) of MMPs and TJP in BBB disruption and ability of MMP inhibitors to improve WNV disease outcome would have considerable therapeutic relevance.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 西尼罗河病毒（WNV）通过蚊子传播，通常会引起人类轻微疾病。然而，在大约 2% 的感染者中，西尼罗河病毒会导致一种致命的脑部疾病，称为脑膜脑炎。目前，尚无治疗西尼罗病毒的药物或预防人类感染西尼罗病毒的疫苗。我们的初步研究表明，西尼罗河病毒通过穿过血脑屏障 (BBB) 进入大脑，并产生介质，例如降解 BBB 的基质金属蛋白酶 (MMP) 酶蛋白。我们的中心假设是，WNV 感染的血液和脑细胞通过环氧合酶-2 (COX-2) 信号通路增加 MMP 的产生，通过降解特定的紧密连接蛋白 (TJP) 介导 BBB 分解。 我们将追求三个具体目标：目标 1 将分析 COX-2 酶及其产物前列腺素 E2 在调节 MMP 水平中的作用。在目标 2 中，我们将评估 WNV 感染的单核细胞降解 TJP 的能力及其在完善的体外 BBB 模型中的迁移。目标 3 将采用小鼠模型来表征 WNV 诱导的 TJP 变化。此外，我们还将确定 MMP 抑制剂防止 BBB 破坏和西尼罗河病毒最终进入中枢神经系统的潜力。我们使用细胞培养和动物模型进行的综合研究将强调 MMP 诱导的 BBB 破坏在西尼罗河病毒疾病发病机制中的作用。对 MMP 和 TJP 在 BBB 破坏中的功能以及 MMP 抑制剂改善 WNV 疾病结果的能力的新见解的发现将具有相当大的治疗意义。