Estrogen reverses progestin-mediated loss of genital mucosal barrier function

雌激素逆转孕激素介导的生殖器粘膜屏障功能丧失

基本信息

批准号：
10458240
负责人：
Thomas L. Cherpes
金额：
$ 70.45万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458240
关键词：
Affect Biological Cell Adhesion Molecules Cell-Cell Adhesion Cells Clinical Research Combined Modality Therapy Confocal Microscopy Contraceptive Agents Contraceptive methods Cream Data Development Dextrans Dose Drug usage Ephrin-A3 Epithelial Estrogen Receptors Estrogens Foundations Genes Genital Genitalia HIV HIV Infections HIV-1 HIV-1 load High Risk Woman Host Defense Human Human Herpesvirus 2 Impairment Infection Infectious Agent Injectable Left Life Macaca Macaca mulatta Mediating Medroxyprogesterone 17-Acetate Modeling Molecular Mucous Membrane Mus Pathway interactions Penetration Peripheral Blood Mononuclear Cell Permeability Pharmaceutical Preparations Pharmacology Placebos Plasma Population Predisposition Progestins Quantitative Reverse Transcriptase PCR Regulation Research SIV Serum Signal Pathway Systemic infection Texas red Tissues Vagina Vaginal Ring Virus Woman Work clinically relevant desmoglein 1 high risk hormonal contraception humanized mouse lucifer yellow microscopic imaging mouse model prevent sexually transmitted virus transmission process

项目摘要

SUMMARY HIV affects more women than any other life-threatening infectious agent. It is most often sexually transmitted, where virus must evade the genital mucosal barrier to cause systemic infection. Clinical studies suggest HIV more easily penetrates this defense among women using the injectable progestin depot-medroxyprogesterone acetate (DMPA). Offering biological plausibility for this possibility, our research group showed that DMPA promoted mouse susceptibility to HSV-2 infection by reducing expression of the cell-cell adhesion molecule desmoglein-1 (DSG1) and increasing genital mucosal permeability. DMPA similarly boosted susceptibility of humanized mice to genital HIV infection. Identifying a potential mechanism for these results, we found DMPA treatment of mice lowered vaginal levels of ephrin A3 (EFNA3); an estrogen (E) receptor target gene shown to promote DSG1 expression in epithelial tissue. Providing clinical relevance for our findings, we showed women initiating DMPA use display changes in ectocervical DSG1 expression and mucosal permeability identical to those seen in mice. Likewise, pharmacologically relevant DMPA doses comparably enhanced genital mucosal permeability in rhesus macaques (RMs). These data newly reveal DMPA impairs mucosal barrier protection. However, using a humanized mouse model of HIV infection, we also uncovered that combined treatment with DMPA and intravaginal (ivag) E blocks virus acquisition by enhancing genital mucosal integrity. These results thus identified an unexpected advantage of hormonal contraceptive strategies that combine use of exogenous progestin and E (i.e., they avert loss of barrier protection caused by progestin use alone). As necessary steps in establishing this approach, this proposal will elucidate mechanisms of E-mediated enhancement of genital mucosal barrier function and define capacity of an E-releasing ivag ring (E-IVR) to protect RMs from genital SIV transmission. Expressly, we will use mice to define E-mediated regulation of EFNA3 pathways that induce DSG1 expression and boost genital mucosal barrier function (Aim 1). We will formulate a RM-sized E-IVR to deliver pharmacologically relevant drug doses, and use these rings to compare EFNA3 and DSG1 expression and mucosal barrier function in RM treated with DMPA, DMPA and placebo IVR, or DMPA and E-IVR (Aim 2). Finally, we will compare genital SIV transmission in RMs administered DMPA, DMPA and placebo IVR, or DMPA and E-IVR with repetitive genital challenges with escalating inoculums of the virus (Aim 3). This work will identify mechanisms by which E induces EFNA3 signaling pathways promoting genital epithelial integrity, and demonstrate that E-IVRs block SIV transmission by abrogating DMPA-mediated weakening of genital mucosal barrier function. These studies will thus deliver important new information in a highly relevant clinical model, and justify exploration of similar contraceptive strategies in populations at high risk for HIV acquisition.

概括艾滋病毒对女性的影响比任何其他危及生命的传染病都要多。它最常见的是性传播，病毒必须逃避生殖器粘膜屏障才能引起全身感染。临床研究表明艾滋病毒使用可注射的孕激素储存剂安宫黄体酮更容易穿透女性的这种防御醋酸盐（DMPA）。我们的研究小组证明 DMPA 为这种可能性提供了生物学上的合理性通过减少细胞间粘附分子的表达来促进小鼠对 HSV-2 感染的易感性 desmoglein-1 (DSG1) 和增加生殖器粘膜通透性。 DMPA 同样会增加对人源化小鼠生殖器艾滋病毒感染。为了确定这些结果的潜在机制，我们发现了 DMPA 对小鼠进行治疗可降低阴道肝配蛋白 A3 (EFNA3) 水平；雌激素 (E) 受体靶基因显示促进上皮组织中 DSG1 的表达。为我们的研究结果提供临床相关性，我们向女性展示了开始使用 DMPA 后，宫颈外 DSG1 表达和粘膜通透性发生变化，与那些在老鼠身上看到的。同样，药理学相关的 DMPA 剂量相对增强了生殖器粘膜恒河猴（RM）的渗透性。这些数据新揭示了 DMPA 会损害粘膜屏障保护。然而，使用 HIV 感染的人源化小鼠模型，我们还发现，联合治疗 DMPA 和阴道内 (ivag) E 通过增强生殖器粘膜完整性来阻止病毒获得。这些结果因此，确定了结合使用外源性激素的激素避孕策略的意想不到的优势孕激素和 E（即，它们可以避免单独使用孕激素导致的屏障保护丧失）。作为必要的步骤在建立这种方法时，该提案将阐明电子介导的生殖器增强机制粘膜屏障功能并定义 E 释放 ivag 环 (E-IVR) 保护 RM 免受生殖器伤害的能力 SIV 传输。明确地说，我们将使用小鼠来定义 E 介导的 EFNA3 途径的调节，从而诱导 DSG1 表达并增强生殖器粘膜屏障功能（目标 1）。我们将制定RM规模的E-IVR 提供药理学相关的药物剂量，并使用这些环来比较 EFNA3 和 DSG1 的表达 DMPA、DMPA 和安慰剂 IVR 或 DMPA 和 E-IVR 治疗的 RM 中的粘膜屏障功能（目标 2）。最后，我们将比较接受 DMPA、DMPA 和安慰剂 IVR 的 RM 中的生殖器 SIV 传播，或 DMPA 和 E-IVR 随着病毒接种量的增加而出现重复的生殖器挑战（目标 3）。这部作品将确定 E 诱导 EFNA3 信号通路促进生殖器上皮完整性的机制，并证明 E-IVR 通过消除 DMPA 介导的生殖器削弱来阻止 SIV 传播粘膜屏障功能。因此，这些研究将在高度相关的临床中提供重要的新信息。模型，并证明在艾滋病毒感染高风险人群中探索类似的避孕策略是合理的。