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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：
10611410
负责人：
RAINA N. FICHOROVA
金额：
$ 78.94万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611410
关键词：
AIDS prevention Africa South of the Sahara Age Anatomy Bacterial Vaginosis Biological Breast Feeding Cervical Circulation Classification Clinical Communication Communities Complex Conduct Clinical Trials Contraceptive Agents Contraceptive Usage Contraceptive methods Development Diagnostic Disease Distant Etiology Exclusion Face Gene Silencing Gene Targeting Genes 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 Vagina Validation Visit Vulnerable Populations Woman Work Zimbabwe acquired immunity bioinformatics tool biomarker identification cervicovaginal circulating microRNA cohort design differential expression disability dysbiosis epigenetic regulation extracellular vesicles functional genomics fundamental research hormonal contraception human female improved infection burden insight metagenome microbiome microbiota new technology novel novel diagnostics novel therapeutics peripheral blood posttranscriptional predictive modeling racial diversity rational design reproductive reproductive tract 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.

目前面临艾滋病毒风险的妇女的避孕选择有限。尽管有证据表明艾滋病毒风险增加获得与孕激素有关的避孕药，主要是DMPA，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是撒哈拉以南非洲最常见的避孕方法--该地区承受着估计占全球艾滋病毒感染负担的70%。阴道微生态失调是艾滋病毒感染的另一个危险因素，在这个艾滋病高发地区的妇女中也更为常见。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使用和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 2）改变的阴道微生物群增强DMPA对宫颈癌的影响免疫力对HC免疫微生物群的分子机制缺乏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。技术.我们提出了一种新的假设驱动的范式来测试微RNA（miRNAs）在风险中的作用，艾滋病病毒感染。由于它们在循环中的稳定性、无处不在的基因沉默功能，小的非编码RNA在控制HIV感染中的重要作用的证据，miRNAs是有吸引力的新的治疗和诊断目标。无与HC和异常相关的miRNA表达信息阴道微生物群是目前可用的。为了填补这一空白的机械理解，我们提出以下建议目的：（1）鉴定与HIV-1获得和先天免疫风险相关的循环异常miRNA，育龄妇女;（2）确定预测HIV风险和免疫失衡的经尿道调节的miRNA （3）鉴定由阴道微生态失调调节的miRNA，与HIV风险相关的全身和粘膜免疫失衡之间的沟通。我们将利用来自乌干达纵向HC-HIV队列的约1000份库存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，代表了不同种族的人群。关于艾滋病毒风险的已知主要因素的全面人口统计、临床和实验室信息将允许稳健的统计建模。我们将使用严格的最先进的技术，转录组学、蛋白质组学和功能基因组学的生物信息学工具，表达的miRNAs和靶基因以及在HIV感染风险中起作用的途径。本研究提供了一个独特的机会，阐明和验证内源性和外源性激素，细菌性阴道病和HIV-1通过分析共同的生物学基础的miRNA 机制等

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Concomitant Imbalances of Systemic and Mucosal Immunity Increase HIV Acquisition Risk.

DOI：
10.1097/qai.0000000000002299
发表时间：
2020-05-01
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
0
作者：
Morrison CS;Chen PL;Yamamoto H;Gao X;Chipato T;Anderson S;Barbieri R;Salata R;Doncel GF;Fichorova RN
通讯作者：
Fichorova RN

The microRNA Cargo of Human Vaginal Extracellular Vesicles Differentiates Parasitic and Pathobiont Infections from Colonization by Homeostatic Bacteria.