MicroRNA Predictors of HIV Risk in Reproductive Age Women

育龄妇女 HIV 风险的 MicroRNA 预测因子

基本信息

批准号：
9795702
负责人：
RAINA N. FICHOROVA
金额：
$ 88.31万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-13 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9795702
关键词：
AIDS prevention Africa South of the Sahara Age Anatomy Bacterial Vaginosis Biological Blood Circulation Breast Feeding Cervical Clinical Communication Communities Complex Conduct Clinical Trials Contraceptive Agents Contraceptive Usage Contraceptive methods Development Diagnostic Disease Distant Etiology Face Gene Silencing Gene Targeting Genes Genetic Transcription Genital system HIV HIV Infections HIV Seronegativity HIV Seropositivity HIV risk HIV-1 Health Hormonal Hormones Immune Immunity Incidence Knowledge Laboratories Luteal Phase Mediating MicroRNAs Mission Modeling Molecular Mucosal Immunity Mucous Membrane Natural Immunity Oral Contraceptives Outcome Pathway interactions Population Heterogeneity Predisposing Factor Predisposition Pregnancy Prevention Preventive Progestins Prospective cohort Proteins Proteomics Public Health RANTES RNA Recurrence Regulation Research Risk Risk Factors Role SLPI gene Sampling Serum Signal Transduction Statistical Models Technology Testing Therapeutic Time Translations Uganda United States United States National Institutes of Health Untranslated RNA Unwanted pregnancy Ursidae Family Vagina Validation Visit Vulnerable Populations Woman Work Zimbabwe bioinformatics tool cervicovaginal circulating microRNA cohort design differential expression disability dysbiosis epigenetic regulation extracellular vesicles functional genomics fundamental research hormonal contraception human female human model improved insight metagenome microbiome microbiota new technology novel novel diagnostics novel therapeutics peripheral blood predictive modeling racial diversity reproductive response transcriptomics transmission process vaginal microbiota

项目摘要

Current contraceptive options for women facing risk of HIV are limited. Despite evidence of increased risk of HIV acquisition associated with progestin-only contraceptives, predominantly DMPA, millions of women around the world continue using DMPA with an estimated >140 million using this or other hormonal contraceptives (HC). Moreover, DMPA is the most common contraceptive method in sub-Saharan Africa – the region that bears an estimated 70% of the global HIV-infection burden. Vaginal dysbiosis, another risk factor for HIV acquisition, is also more common in women in this high HIV incidence region. Insights from our research gained in one of the largest prospective cohorts designed to investigate the association between HC use and HIV acquisition (HC- HIV study), support the following paradigms: 1) DMPA users develop aberrant cervical and systemic immunity that precedes HIV seroconversion and 2) altered vaginal microbiota potentiates DMPA effects on cervical immunity. The lack of understanding of the molecular mechanisms underlying the HC-immunity-microbiota interactions leading to increased HIV susceptibility is limiting efforts to design safer contraceptive and preventive technologies. We propose a novel hypothesis-driven paradigm to test the role of micro-RNAs (miRNAs) in risk of HIV acquisition. Because of their stability in the circulation, ubiquitous gene silencing function, and emerging evidence of important roles of small non-coding RNAs in controlling HIV infection, miRNAs are attractive novel therapeutic and diagnostic targets. No information on miRNA expression in association with HC and abnormal vaginal microbiota is currently available. To fill this gap in mechanistic understanding, we propose the following aims: (1) Identify circulating aberrant miRNAs associated with risk of HIV-1 acquisition and innate immunity in reproductive age women; (2) Identify hormonally regulated miRNAs predictive of HIV risk and immune imbalance that precedes HIV seroconversion; (3) Identify miRNAs regulated by vaginal dysbiosis that may facilitate communication between systemic and mucosal immunity imbalance associated with HIV risk. We will utilize ~1000 banked sera and cervicovaginal secretions from the longitudinal HC-HIV cohorts in Uganda and Zimbabwe and four clinical trials conducted in the United States representing a racially diverse population. Comprehensive demographic, clinical and laboratory information available on known major factors for HIV risk in these cohorts will allow robust statistical modeling. We will use rigorous state-of-the-art technologies and bioinformatics tools for transcriptomic, proteomic and functional genomics to generate profiles of differentially expressed miRNAs and targeted genes and pathways with roles in the risk of HIV acquisition. This research provides a unique opportunity to elucidate and validate the complex associations between endogenous and exogenous hormones, bacterial vaginosis and HIV-1 through analysis of miRNAs underlying shared biological mechanisms.

尽管有证据表明艾滋病毒风险增加，但目前面临艾滋病毒风险的妇女的避孕选择仍然有限。与纯孕激素避孕药（主要是 DMPA）相关的购买，全球数以百万计的女性全世界继续使用 DMPA，估计有超过 1.4 亿人使用这种或其他激素避孕药 (HC)。此外，DMPA 是撒哈拉以南非洲地区最常见的避孕方法，该地区是据估计，全球 70% 的艾滋病毒感染负担是阴道菌群失调，这是感染艾滋病毒的另一个危险因素。在这个艾滋病毒高发地区的女性中也更为常见，这是我们从一项研究中获得的见解。最大的前瞻性队列旨在调查 HC 使用与 HIV 感染之间的关联（HC- HIV 研究），支持以下范例：1）DMPA 使用者产生异常的宫颈和全身免疫发生在 HIV 血清转化之前，并且 2) 改变的阴道微生物群增强了 DMPA 对宫颈的影响缺乏对 HC 免疫微生物群的分子机制的了解。导致艾滋病毒易感性增加的相互作用限制了设计更安全的避孕和预防措施的努力我们提出了一种新的假设驱动范式来测试 micro-RNA (miRNA) 在风险中的作用。由于它们在循环中的稳定性、普遍存在的基因沉默功能以及新兴的HIV感染。小非编码 RNA 在控制 HIV 感染中发挥重要作用的证据表明，miRNA 是有吸引力的新型药物没有与 HC 和异常相关的 miRNA 表达的信息。为了填补这一机制理解的空白，我们提出以下建议。目标：(1) 识别与 HIV-1 获得风险和先天免疫相关的循环异常 miRNA 育龄妇女；(2) 识别可预测 HIV 风险和免疫失衡的激素调节 miRNA (3) 鉴定受阴道菌群失调调节的 miRNA，这可能有助于我们将利用与艾滋病毒风险相关的系统和粘膜免疫失衡之间的沟通。约 1000 份储存的血清和宫颈阴道分泌物，来自乌干达和 HC-HIV 纵向队列津巴布韦和在美国进行的四项临床试验代表了不同种族的人群。有关艾滋病毒风险的已知主要因素的全面人口统计、临床和实验室信息在这些队列中，我们将使用严格的最先进的技术和用于转录组、蛋白质组和功能基因组学的生物信息学工具，可生成差异谱图这项研究揭示了表达的 miRNA 以及靶基因和通路在 HIV 感染风险中的作用。提供了一个独特的机会来阐明和验证内源性和通过分析共享生物学基础的 miRNA 来了解外源性激素、细菌性阴道病和 HIV-1 机制。