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

感染艾滋病毒的吸烟者加速肺气肿：细胞外囊泡的作用

• 批准号: 9321321
• 负责人: Philip T Diaz
• 金额: $ 51.67万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321321
• 关键词: Adverse effects; Age; Aging; Biological; Biological Markers; Blood; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell physiology; Chronic Disease; Chronic Obstructive Airway Disease; Data; Development; Diffusion; Disease; General Population; HIV; HIV Seropositivity; High Prevalence; Homeostasis; Human; Impairment; Incidence; Individual; Investigation; Knowledge; Light; Lung; Lung diseases; MicroRNAs; Minority; Mitogen-Activated Protein Kinases; Molecular Profiling; Oxidative Stress; Pathogenesis; Pathway interactions; Pattern; Persons; Phenotype; Physiological; Play; Population; Predisposition; Prevalence; Protease Inhibitor; Proteins; Proteomics; Pulmonary Emphysema; Risk; Role; Smoker; Smoking; Specimen; Testing; Time; Transforming Growth Factor beta; base; biological adaptation to stress; burden of illness; cigarette smoking; cigarette smoking; density; extracellular vesicles; insight; novel therapeutic intervention; novel therapeutics; protein expression; public health relevance; surfactant

 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.

 描述（由申请人提供）：我们和其他人的观察结果很重要，即与非艾滋病毒感染人群相比，艾滋病毒感染人群中慢性阻塞性肺病的发病率更高，特别是，感染艾滋病毒的吸烟者似乎更容易患肺气肿。初步数据表明，在患有或不患有肺气肿的艾滋病毒感染者中，细胞外囊泡（EV）的蛋白质表达模式发生了变化。 HIV 相关肺气肿中可能失调的生物途径，包括氧化应激反应、抗蛋白酶机制和表面活性剂稳态，初步数据还表明，microRNA (miRNA) 的失调可能是发病机制中涉及的生物途径的关键驱动因素。肺气肿的相关性，包括氧化应激、TGF beta、Map 激酶和 Wnt 通路。在这项研究中，我们将基于这些观察结果并建议检查 EV 的相关性。我们将通过系统检查和整合 EV 中的蛋白质组和 miRNA 模式来实现这一目标，我们将追求以下具体目标：开发具体目标 1：测试。假设与 HIV 诱导的肺气肿相关的肺 EV 蛋白表达谱的改变可以与 HIV 未感染人群中与肺气肿相关的途径区分开。 具体目标 2：研究肺 EV miRNA 表达是否驱动。通过失调的蛋白质确定了导致 HIV 相关肺气肿发病机制的独特生物网络。 具体目标 3：检验基于循环 EV 的生物标志物可能与感染 HIV 的吸烟者发生肺损伤风险增加相关的假设。将为我们提供有关艾滋病毒相关肺部疾病的知识，并可能为肺气肿病理学提供重要的见解。