Plasma miRNA Biomarkers of HIV/SIV CNS Disease

HIV/SIV CNS 疾病的血浆 miRNA 生物标志物

• 批准号: 8916196
• 负责人: JANICE E CLEMENTS
• 金额: $ 53.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916196
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Acute; Affect; Alzheimer' s Disease; Animal Model; Biological Assay; Biological Markers; Blood Cells; Brain; Brain region; CD4 Positive T Lymphocytes; CNS processing; Cell Count; Central Nervous System Diseases; Cerebrospinal Fluid; Characteristics; Cognitive; Communicable Diseases; Dementia; Development; Diagnosis; Diagnostic; Disease; Disease Outcome; Encephalitis; Epidemic; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Health; Highly Active Antiretroviral Therapy; Human; Immune response; Impairment; Incidence; Individual; Infection; Inflammation Mediators; Inflammatory; Interferons; Life; Link; Lipoproteins; Longevity; Macaca; Malignant Neoplasms; Measures; Mediating; Methods; MicroRNAs; Minor; Modeling; Molds; Neurocognitive Deficit; Neurologic; Pathogenesis; Pathway interactions; Patients; Peripheral; Plasma; Predisposition; Prevalence; Process; Regimen; Regulation; Role; SIV; Sampling; Severities; Severity of illness; Signal Transduction; Small RNA; Source; Staging; Therapeutic; Untranslated RNA; Vesicle; Viral; Viral Load result; antiretroviral therapy; base; brain cell; circulating microRNA; cohort; cytokine; differential expression; insight; motor disorder; nervous system disorder; neurocognitive disorder; new therapeutic target; novel; particle; prognostic; prognostic tool; protein complex; response; senescence; stem; tool

DESCRIPTION (provided by applicant): Antiretroviral therapy (ART) has dramatically changed the HIV epidemic, delaying disease, prolonging life, and altering HIV-associated neurocognitive disorders (HAND) from encephalitis/dementia (HAD) to milder but nevertheless debilitating disorders such as minor cognitive/motor disorder (MC/MD) and asymptomatic neurocognitive impairment (ANI). However, despite ART, HAND prevalence has increased with patient longevity, and mild to moderate disorders are diagnosed in 50-60% of ART patients. There are currently no biomarkers used to diagnose or predict HAND. Plasma biomarkers developed for AIDS (viral load and CD4+ T cell count), were essential in developing treatment paradigms. It is critical to develop similarly sensitive, reliable, and accessible biomarkers for HAND. MicroRNAs (miRNAs), which are linked to various diseases including cancers and Alzheimer's disease, are a promising source of novel biomarkers. These small, non- coding RNAs are abundant and stable in plasma, providing a unique opportunity for biomarker discovery. Reflecting disease states, plasma miRNAs may also present novel therapeutic targets. Using our SIV/macaque model of CNS disease and ART, we identified a plasma miRNA signature of acute infection and CNS disease-predictive miRNAs with roles in neurologic disorders and/or senescence. Here, we will identify plasma miRNA biomarkers during different stages of infection (Aim 1); characterize miRNA profiles in cerebrospinal fluid (CSF) and brain during infection; and identify miRNAs that predict the development of CNS disease (untreated macaques) or correlate with persistent levels of inflammatory cytokines in brain of ART treated macaques (Aim 2). We will extend these studies to HIV-infected individuals with HAND using matched plasma and CSF from the NorthEast AIDS Dementia (NEAD) cohort to identify and validate plasma miRNA biomarkers for HAD, MC/MD, and ANI (Aim 3). Finally, plasma miRNA biomarkers will be studied in brain and specific plasma fractions to identify cellular sources of circulating miRNAs and the vehicles (vesicles, lipoprotein particles, protein complexes) of disease-predictive plasma miRNAs (Aim 4). The goal of these studies is to identify plasma miRNA biomarkers that diagnose and predict the development of HAND and that provide insights into HAND pathogenesis. Our hypothesis is that a unique combination of differentially expressed plasma miRNAs will be diagnostic for HIV/SIV infection stage, predictive of CNS disease, and reflective of the impact of both viral and host responses in brain. Some of these miRNAs will originate from brain, while others will stem from peripheral processes that affect or parallel CNS processes. Results of these studies will represent a substantial advance in the understanding of how plasma miRNAs originate and circulate during health and infectious disease. Importantly, our findings will have significance fo HAND diagnostics and therapeutics, facilitating functional characterization of pathways that are dysregulated in brain during the development of HAND: potential targets of small-RNA based therapeutics.

描述（由申请人提供）： 抗逆转录病毒疗法（ART）已大大改变了HIV流行病，延迟疾病，延长寿命，并改变了与HIV相关的神经认知障碍（手）从脑炎/痴呆症（患有）到温和的疾病，但诸如MC次要疾病（MC）（MC次要/运动障碍）（MC）（MC） /MD）和无症状的神经认知障碍（ANI）。然而，尽管有艺术，但患者的寿命仍增加了，并且在50-60％的艺术患者中被诊断出轻度至中度的疾病。当前没有用于诊断或预测手的生物标志物。为艾滋病开发的血浆生物标志物（病毒载量和CD4+ T细胞计数）对于开发治疗范例至关重要。为手开发类似敏感，可靠和可访问的生物标志物至关重要。与包括癌症和阿尔茨海默氏病在内的各种疾病有关的microRNA（miRNA）是新型生物标志物的有前途的来源。这些小的非编码RNA在等离子体中丰富而稳定，为生物标志物发现提供了独特的机会。反映疾病状态的血浆miRNA也可能提出新的治疗靶标。使用我们的CNS疾病和ART的SIV/猕猴模型，我们确定了急性感染和CNS疾病预测性miRNA的血浆miRNA特征，在神经系统疾病和/或衰老中起着作用。在这里，我们将在不同感染阶段鉴定等离子miRNA生物标志物（AIM 1）；在感染过程中表征脑脊液（CSF）和大脑中的miRNA谱；并确定预测中枢神经系统疾病发展（未处理猕猴）或与ART治疗猕猴大脑中持续水平的炎性细胞因子水平相关的miRNA（AIM 2）。我们将使用来自东北艾滋病痴呆症（NEAD）队列的匹配的血浆和CSF将这些研究扩展到艾滋病毒感染的个体，以识别和验证血浆miRNA生物标志物的HAD，MC/MD和ANI（AIM 3）。最后，将在大脑和特定的血浆级分中研究血浆miRNA生物标志物，以鉴定循环中的miRNA和疾病预测性血浆miRNA的车辆（囊泡，脂蛋白颗粒，蛋白质复合物）的细胞来源（AIM 4）。 这些研究的目的是鉴定血浆miRNA生物标志物，以诊断和预测手的发展，并提供对手部发病机理的见解。我们的假设是，差异表达的血浆miRNA的独特组合将是HIV/SIV感染阶段的诊断，预测了CNS疾病，并反映了病毒和宿主反应在大脑中的影响。这些miRNA中的一些将来自大脑，而另一些则源于影响或平行CNS过程的外围过程。这些研究的结果将在理解血浆miRNA在健康和传染病期间如何产生和循环的结果大大进步。重要的是，我们的发现将在手动诊断和治疗学方面具有重要意义，从而促进了手发展过程中大脑中途径失调的途径的功能表征：基于小RNA的疗法的潜在靶标。