The role of the CMV-associated reactive oxygen species in age-related

CMV 相关活性氧在年龄相关性中的作用

• 批准号: 10313478
• 负责人: Kevin John Zwezdaryk
• 金额: $ 2.9万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313478
• 关键词: role; CMV; associated; reactive; oxygen

Cytomegalovirus (CMV) infection is linked to increased risk of frailty and death in older populations. Despite being correlated to age-related disease, a mechanism linking CMV infection and unhealthy aging is unknown. We have recently reported that CMV infection alters mitochondrial structure and function promoting oxidative stress. CMV infection increases electron transport chain (ETC) activity resulting in elevate reactive oxygen species (ROS). Excess ROSis known to damage proteins and lipids and can induce mutations in mitochondrial DNA. Mitochondrial dysfunction is recognized as a hallmark of aging. This COBRE proposal is designed to identify mechanisms by which CMV exacerbates ROS leak, contributing to age-associated mitochondrial dysfunction. To test our hypothesis, we will integrate multiple model systems to delineate the role of CMV induced ROSon lipid peroxide levels (Specific Aim 1), the contribution of CMV-associated ROSproduction on endogenous mtDNA mutations (Specific Aim 2) and the contribution of lipid peroxides generated during CMV infection to exacerbate aged associated mitochondrial dysfunction (Specific Aim 3). CMV infection occurs for the lifetime of the host and reactivation is frequent throughout the hosts life. This suggests that oxidative stress may promote mitochondrial dysfunction that can accumulate over time. Our aims are designed to generate strong preliminary data to support NIH R01 grant applications. The manipulation of host mitochondria by CMV may clarify the role of CMV as a modulator that promotes unhealthy aging. Thus, fully understanding how a chronic viral infection can exacerbate aging represents a significant public health issue and novel therapeutic approach to both healthy aging and antiviral therapy.

巨细胞病毒（CMV）感染与老年人虚弱和死亡风险增加有关。尽管巨细胞病毒感染与年龄相关疾病相关，但巨细胞病毒感染与不健康衰老之间的联系机制尚不清楚。我们最近报道，CMV 感染改变线粒体结构和功能，促进氧化应激。 CMV 感染增加电子传递链 (ETC) 活性，导致活性氧 (ROS) 升高。已知过量的 RO 会损害蛋白质和脂质，并可能诱导线粒体 DNA 突变。线粒体功能障碍被认为是衰老的标志。该 COBRE 提案旨在确定 CMV 加剧 ROS 泄漏、导致与年龄相关的线粒体功能障碍的机制。为了检验我们的假设，我们将整合多个模型系统来描述 CMV 诱导的 ROSon 脂质过氧化物水平的作用（具体目标 1）、CMV 相关 ROS 产生对内源性 mtDNA 突变的贡献（具体目标 2）以及 CMV 感染期间产生的脂质过氧化物对加剧衰老相关线粒体功能障碍的贡献（具体目标 3）。 CMV 感染在宿主的一生中都会发生，并且在宿主的一生中重新激活很频繁。这表明氧化应激可能会促进线粒体功能障碍，并随着时间的推移而积累。我们的目标是生成强有力的初步数据来支持 NIH R01 拨款申请。 CMV 对宿主线粒体的操纵可能阐明 CMV 作为促进不健康衰老的调节剂的作用。因此，充分了解慢性病毒感染如何加剧衰老是一个重大的公共卫生问题，也是健康衰老和抗病毒治疗的新治疗方法。