Extracellular Vesicle and Extracellular RNA Biomarkers of HIV-1 Central Nervous System Pathogenesis and Cigarette Use

HIV-1 中枢神经系统发病机制和香烟使用的细胞外囊泡和细胞外 RNA 生物标志物

• 批准号: 10217079
• 负责人: Kenneth W Witwer
• 金额: $ 63.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217079
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Astrocytes; Attention; Back; Benchmarking; Biological; Biological Markers; Biology; Brain; CD4 Positive T Lymphocytes; Catalogs; Categories; Cell Count; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Diagnosis; Diagnostic; Disease; Disease model; General Population; Goals; HIV; HIV antiretroviral; HIV-1; HIV-associated neurocognitive disorder; Human; Individual; Inflammation; Learning; Liquid substance; Literature; Longevity; Measurement; MicroRNAs; Microglia; Modeling; Molecular Profiling; Morbidity - disease rate; Morphologic artifacts; Nerve Degeneration; Neuraxis; Neurons; Pathogenesis; Phenotype; Plasma; Population; Process; RNA; RNA analysis; Reproducibility; Research; Role; Sampling; Smoking; Substance Use Disorder; Techniques; Technology; Testing; Time; Tissue Sample; Tissues; Tobacco smoking behavior; Tobacco use; Untranslated RNA; Validation; Vesicle; Viral Load result; antiretroviral therapy; body system; brain tissue; candidate identification; candidate marker; cigarette smoke; cigarette smoking; circular RNA; cohort; comorbidity; comparative; extracellular; extracellular vesicles; improved; innovation; nervous system disorder; nonhuman primate; novel; novel marker; prognostic; sample archive; senescence; tool; transcriptome sequencing; virology

ABSTRACT The HIV-associated neurocognitive disorders (HAND) and other neurologic disorders are predicted to affect a majority of HIV-infected individuals at some time during the lifespan. These disorders occur despite effective virologic suppression by antiretroviral therapy (ART). Yet few established biological markers. Recalling that plasma biomarkers developed for AIDS (viral load and CD4+ T cell count) were essential in developing treatment paradigms for AIDS, an intensified research focus on biomarkers of neurologic disease is warranted. Improved biomarkers may be particularly important when substance use disorders (SUDs) are comorbid with HIV disease. Among HIV+ individuals, cigarette smoking is several times more prevalent than in the general population and contributes to inflammation and senescence processes that exacerbate pathogenesis in multiple organ systems. Promising classes of biomarkers include stable extracellular RNAs (exRNAs), a portion of which are packaged into extracellular vesicles (EVs) that can leave tissue such as brain to be found in easily accessed biological fluids. These entities receive increasing attention as markers of neurologic disease because of roles in neurodegeneration and (for EVs) because they can be traced back to a cell or tissue of origin. Two categories of exRNA are particularly attractive because of their extraordinary stability: microRNAs (miRNAs) and circular RNAs (circRNAs). miRNAs have been studied in HIV disease and SUDs, but not in EVs of brain tissue, and almost nothing is known about circRNAs in HIV-1 pathogenesis or SUDs. In this project, we will develop a catalog of biomarkers of HIV-1 pathogenesis and cigarette use and identify how cigarette use may complicate interpretation of biomarker tests. Archived samples from a well characterized animal model and human cohorts will be tested to identify and validate candidate biomarkers. Our expertise is in HIV-1 disease and animal models; biomarkers of neurologic disease; EV techniques and biology; and noncoding RNAs. We will first use a novel tissue EV isolation technique to seek candidate molecular signatures of EVs and exRNA in brain tissue (Aim 1), and then investigate EV and exRNA signatures in matched, longitudinally collected cerebrospinal fluid and blood plasma (Aim 2). Importantly, Aim 3 investigates human samples in parallel. the project will address current gaps in the literature in rigorous and reproducible fashion by ruling out common artifacts of EV and exRNA analysis and through cutting edge confirmation of the identity of isolated EVs. Overall, we hypothesize that brain-derived EVs and their most stable exRNA cargo, miRNAs and circRNAs, serve as biomarkers of HIV-associated neurologic disorders. Since some markers will also be associated with cigarette smoking, tobacco use will be investigated for possible interfering effects on measurement of neurologic disease biomarkers.

抽象的 艾滋病毒相关的神经认知障碍（手）和其他神经系统疾病被预测会影响 在寿命中的某个时候，大多数艾滋病毒感染者。这些疾病尽管有效 抗逆转录病毒疗法（ART）的病毒抑制。但很少有建立的生物标记。回想一下 为艾滋病开发的血浆生物标志物（病毒载荷和CD4+ T细胞计数）对于发展至关重要 有必要对艾滋病的治疗范例，对神经系统疾病的生物标志物进行的加强研究是有必要的。 当物质使用障碍（SUD）合并时，改善的生物标志物可能特别重要 艾滋病毒疾病。在艾滋病毒+个人中，吸烟比一般多倍 人口并有助于加剧发病机理的炎症和衰老过程 多器官系统。有前途的生物标志物包括稳定的细胞外RNA（EXRNA），A 其中的一部分被包装成细胞外囊泡（EV），这些囊泡可能会留下组织（例如大脑） 在易于进入的生物流体中发现。作为神经系统的标志，这些实体受到越来越多的关注 疾病是由于神经退行性中的作用而（对于电动汽车），因为它们可以追溯到细胞或 原产组织。两类Exrna由于其非凡稳定性特别有吸引力： microRNA（miRNA）和圆形RNA（CIRCRNA）。 miRNA已在HIV疾病和泡沫中进行了研究， 但是，在脑组织的电动汽车中没有，几乎没有关于HIV-1发病机理或SUD的CIRCRNA的了解。在 这个项目，我们将开发HIV-1发病机理和香烟使用的生物标志物的目录，并确定如何 香烟使用可能会使生物标志物测试的解释复杂化。归档的样本来自一个良好的特征 动物模型和人类人群将进行测试以识别和验证候选生物标志物。我们的专业知识是 在HIV-1疾病和动物模型中；神经疾病的生物标志物；电动汽车技术和生物学；和 非编码RNA。我们将首先使用一种新型的组织EV隔离技术来寻求候选分子 EV和EXRNA在脑组织中的特征（AIM 1），然后研究EV和EXRNA签名 匹配，纵向收集的脑脊液和血浆（AIM 2）。重要的是，AIM 3调查 人类样本并联。该项目将解决严格且可重复的文献中的当前差距 通过排除EV和EXRNA分析的常见人工制品以及通过最先进的确认 孤立的电动汽车的身份。总体而言，我们假设大脑衍生的电动汽车及其最稳定的exrna 货物，miRNA和CIRCRNA是与HIV相关神经系统疾病的生物标志物。自从有些 标记也将与吸烟，烟草使用有关，以进行干扰 对神经疾病生物标志物测量的影响。