Accelerated emphysema in HIV-infected smokers: the role of extracellular vesicles

 描述(由申请人提供)：我们和其他人已经做出了重要的观察，与未感染艾滋病毒的人群相比，感染艾滋病毒的人群中COPD的发病率更高。特别是，感染艾滋病毒的吸烟者似乎容易患上一种肺气肿表型，其生理特征是扩散障碍。初步数据表明，在患有和不患有肺气肿的HIV感染吸烟者中，细胞外小泡(EV)中的蛋白质表达模式发生了变化。这些模式涉及许多可能在HIV相关肺气肿中调节失调的生物途径，包括氧化应激反应、抗蛋白酶机制和表面活性物质动态平衡。初步数据还表明，microRNAs(MiRNAs)的解除调控可能是肺气肿发病机制中涉及的生物途径的关键驱动因素，包括氧化应激、转化生长因子β、MAPK和Wnt途径。在这项研究中，我们将建立在这些观察的基础上，并建议通过开发HIV相关肺气肿的功能性miRNA签名来检查基于EV的生物标记物的相关性。我们将通过系统地检查和整合EVS中的蛋白质组和miRNA模式来做到这一点。为了实现这一目标，我们将追求以下具体目标：具体目标1：检验一种假设，即与HIV诱导的肺气肿相关的肺EV蛋白表达谱的变化可以与未感染HIV的人群中与肺气肿相关的那些途径区分开来。具体目的2：调查肺EV miRNA表达是否驱动通过非调控蛋白识别的不同生物网络，从而促进HIV相关性肺气肿的发病。具体目标3：验证基于EV的循环生物标记物可能与HIV感染吸烟者肺损伤风险增加相关的假设。这个项目的成功完成将使我们了解艾滋病毒相关的肺部疾病，并可能为肺气肿的病理生物学提供重要的见解。

 DESCRIPTION (provided by applicant): We and others have made the important observation that the incidence of COPD is higher among the HIV infected population compared to the non-HIV infected population. In particular, HIV-infected smokers appear to be susceptible to an emphysema phenotype characterized physiologically by diffusion impairment. Preliminary data suggests that there are altered protein expression patterns in extracellular vesicles (EV) among HIV-infected smokers with and without emphysema. These patterns implicate a number of biologic pathways that may be dysregulated in HIV-associated emphysema, including the oxidative stress response, anti-protease mechanisms and surfactant homeostasis. Preliminary data also demonstrates that deregulation of microRNAs (miRNAs) may be a key driver of biological pathways implicated in the pathogenesis of emphysema, including oxidative stress, TGF beta, Map Kinase and Wnt pathways. In this investigation we will build on these observations and propose to examine the relevance of EV based biomarkers by developing a functional miRNA signature for HIV associated emphysema. We will do this by the systematic examination and integration of both proteomic and miRNA patterns within EVs. To achieve this objective we will pursue the following specific aims: Specific Aim 1: To test the hypothesis that alterations in lung EV protein expression profiles associated with HIV-induced emphysema can be distinguished from those pathways associated with emphysema in the HIV- uninfected population. Specific Aim 2: To investigate if lung EV miRNA expression drives distinct biological networks identified through deregulated proteins contributing to the pathogenesis of HIV associated emphysema. Specific Aim 3: To test the hypothesis that circulating EV based biomarkers may be associated with increased risk of lung damage occurring in HIV-infected smokers. Successful completion of this project will inform our knowledge of HIV-related lung disease and may also provide important insight into emphysema pathobiology.