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

巨细胞病毒(CMV)感染与老年人群中虚弱和死亡的风险增加有关。尽管与年龄相关的疾病相关，但CMV感染和不健康衰老之间的联系机制尚不清楚。我们最近报道，CMV感染改变了线粒体的结构和功能，促进了氧化应激。CMV感染增加了电子传递链(ETC)的活性，导致活性氧(ROS)升高。已知过量的ROS会损害蛋白质和脂质，并可能导致线粒体DNA突变。线粒体功能障碍被认为是衰老的标志。这项Cobre建议旨在确定CMV加剧ROS泄漏，导致年龄相关线粒体功能障碍的机制。为了验证我们的假设，我们将整合多个模型系统来描述CMV诱导的Roson脂质过氧化水平的作用(特定目标1)，CMV相关的ROS产生对内源性mtDNA突变的贡献(特定目标2)，以及在CMV感染过程中产生的过氧化脂质对加剧衰老相关线粒体功能障碍的贡献(特定目标3)。CMV感染在寄主的整个生命周期内发生，并且在寄主的整个生命周期中频繁地重新激活。这表明，氧化应激可能会促进线粒体功能障碍，这种功能障碍会随着时间的推移而积累。我们的目标是生成强大的初步数据，以支持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器的作用。因此，充分了解慢性病毒感染如何加剧衰老是一个重要的公共卫生问题，也是健康老龄化和抗病毒治疗的新的治疗方法。

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.