MECHANISMS BY WHICH CMV MAY CONTRIBUTE TO ATHEROGENESIS AND RESTENOSIS

CMV 导致动脉粥样硬化和再狭窄的机制

• 批准号: 6162765
• 负责人: J ZHU
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162765
• 关键词: Herpesviridae disease; Herpesviridae vaccine; atherosclerosis; cell migration; cellular immunity; cytomegalovirus; gene targeting; human tissue; humoral immunity; interleukin 12; laboratory mouse; laboratory rat; phenotype; restenosis; transfection; vascular smooth muscle

Increasing evidence suggests human cytomegalovirus (HCMV) infection contributes to the development of atherosclerosis. Because the type of immune response (cellular vs humoral) to infectious agents can determine disease expression or containment, we are in the process of testing the following hypotheses: 1) In healthy and atherosclerotic populations there is a spectrum of humoral vs cellular immunodominant responses to HCMV infection. 2) An immunodominant cellular phenotype conveys resistance to coronary artery disease, while an immunodominant humoral phenotype conveys susceptibility. If these hypotheses are correct, we will investigate whether the susceptible humoral phenotype can be switched to the resistant cellular phenotype with gene therapy, using adenoviral vectors that contain the IL-12 transgene. (This cytokine has been shown, in other settings, to be able to switch a humoral to a cellular immunodominant response). We are also investigating the vaccine straties against CMV and whether such strategies can reduce CMV-mediated vascular disease. Specifically: 1) We have demonstrated that CMV infection of rats increases the response to vascular injury. We are now initiating studies to determine whether vaccination with a cDNA encoding rat CMV IE proteins will prevent the neointimal response to vascular injury in the rat carotid-injury model. 2) We are initiating studies to determine whether ApoE knockout mice, which develop spontaneous atherosclerosis, will develop an increased rate of atherogenesis when infected with mouse CMV. If this turns out to be the case, we will embark on gene delivery studies to determine whether vaccine therapy, augmented by cytokine gene delivery, will protect against CMV-mediated atherogenesis. Mechanisms by which HCMV may increase SMC accumulation a) Can HCMV infection inhibit apoptosis in SMCs and, if so: 1) does it inhibit p53-dependent or independent pathways?; 2) which viral gene products are responsible for anti-apoptotic effects? b) SMC migration from the media and/or adventitia is believed to play an important role in the development of both restenosis and atherosclerosis. Does HCMV infection of SMCs increase the ability of SMCs to migrate? The immune response to HCMV a) Immunodominant cellular and humoral responses to HCMV and their relation to vascular disease.

越来越多的证据表明人类巨细胞病毒(HCMV)感染 有助于动脉粥样硬化的发展。因为这种类型的 对感染性病原体的免疫反应(细胞和体液)可以决定 疾病的表达或遏制，我们正在测试 以下是假设： 1)在健康和动脉粥样硬化人群中，有一系列 对HCMV感染的体液免疫显性反应与细胞免疫显性反应。 2)免疫显性细胞表型传递对冠状动脉的抵抗力 动脉疾病，而免疫显性体液表型传达 敏感度。 如果这些假设是正确的，我们将调查 敏感的体液表型可以转换为抗性细胞 表型与基因治疗，使用腺病毒载体，其中包含 IL-12转基因。(在其他情况下，这种细胞因子已被显示为 能够将体液反应转换为细胞免疫显性反应)。 我们还在调查针对CMV的疫苗层，以及 这样的策略可以减少巨细胞病毒介导的血管疾病。具体地说，就是： 1)我们已经证明，大鼠感染巨细胞病毒会增加 对血管损伤的反应。我们现在正在启动研究，以确定 用编码大鼠CMV IE蛋白的cDNA接种是否会 预防大鼠血管损伤后的新生内膜反应 颈动脉损伤模型。 2)我们正在启动研究，以确定ApoE基因敲除小鼠， 发展为自发性动脉粥样硬化的人，会发展为 感染小鼠巨细胞病毒时动脉粥样硬化的发生率。如果结果是这样 在这种情况下，我们将着手进行基因传递研究，以确定 通过细胞因子基因传递加强的疫苗治疗是否会 预防巨细胞病毒介导的动脉粥样硬化形成。 人巨细胞病毒促进SMC蓄积的机制 A)人巨细胞病毒感染能否抑制平滑肌细胞的凋亡，如果是： 1)它是否抑制P53依赖或独立的通路？ 2)哪些病毒基因产物负责抗细胞凋亡 效果呢？ B)SMC从介质和/或外膜的迁移被认为起了作用 在再狭窄和再狭窄的发展中起重要作用 动脉硬化。人巨细胞病毒感染血管内皮细胞的能力增强吗 中小企业要迁移吗？ 人巨细胞病毒的免疫应答 A)对巨细胞病毒的免疫显性细胞和体液反应及其 与血管疾病有关。