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

巨细胞病毒（CMV）感染与老年人虚弱和死亡的风险增加有关。尽管与年龄相关的疾病有关，但CMV感染和不健康衰老的机制尚不清楚。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ROS会破坏蛋白质和脂质，并可诱导线粒体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泄漏的机制，从而导致年龄相关的线粒体功能障碍。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ROS对脂质过氧化物水平的作用（具体目标1），CMV相关的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老年相关线粒体功能障碍的贡献（具体目标3）。CMV感染发生在宿主的一生中，并且在宿主的整个生命中经常重新激活。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，以支持NIH R01资助申请。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要的公共卫生问题，也是健康衰老和抗病毒治疗的新治疗方法。

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.