MicroRNA Predictors of HIV Risk in Reproductive Age Women

育龄妇女 HIV 风险的 MicroRNA 预测因子

• 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
• 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

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.

面临艾滋病毒风险的妇女的当前避孕措施是有限的。尽管有艾滋病毒风险增加的证据 与仅孕激素避孕药，主要是DMPA，数百万妇女有关的获取 使用DMPA，使用此或其他马避孕药（HC），世界继续使用DMPA估计> 1.4亿。 此外，DMPA是撒哈拉以南非洲最常见的避孕方法 - 估计全球艾滋病毒感染的70％。阴道营养不良是艾滋病毒收购的另一个危险因素，是 在这个高艾滋病毒事件地区的女性中也更为常见。从我们的研究中获得的见解 最大的前瞻性队列旨在调查HC使用与艾滋病毒收购之间的关联（HC- HIV研究），支持以下范例：1）DMPA用户发展异常和全身免疫力 在HIV血清转化和2）改变阴道微生物菌对DMPA对宫颈的影响的改变 免疫。缺乏对HC-免疫性 - 微生物的分子机制的了解 相互作用导致HIV敏感性提高是限制设计更安全和预防性的努力 技术。我们提出了一种新型假设驱动的范例来测试微RNA（miRNA）在风险中的作用 艾滋病毒收购。由于它们在循环中的稳定性，无处不在的基因沉默功能和出现 小型非编码RNA在控制HIV感染中的重要作用的证据，miRNA是吸引人的新型 治疗和诊断靶标。没有关于与HC和异常相关的miRNA表达的信息 当前可用阴道微生物群。为了填补机械理解的这一空白，我们提出以下内容 目的：（1）确定与HIV-1获取风险和先天免疫相关的循环异常miRNA 生殖年龄妇女； （2）确定荷尔蒙调节的miRNA预测HIV风险和免疫感像 在HIV血清转化之前； （3）确定可能有助于促进的阴道失调调节的miRNA 与艾滋病毒风险相关的系统性和粘膜免疫失衡之间的通信。我们将利用 〜1000个来自乌干达纵向HC-HIV队列的血清和宫颈阴道分泌物 津巴布韦和在美国进行的四项临床试验代表大致多样化的人群。 有关艾滋病毒风险的已知主要因素可获得的全面人口，临床和实验室信息 在这些队列中，将允许强大的统计建模。我们将使用严格的最先进的技术和 用于转录组，蛋白质组学和功能基因组学的生物信息学工具，以生成差异的谱图 表达miRNA和靶向基因和途径，在艾滋病毒获取风险中具有作用。这项研究 提供了一个独特的机会来阐明和验证内源性和之间的复杂关联 通过分析共享生物学的miRNA，外源激素，阴道细菌和HIV-1 机制。