Understanding the effects of cross-sex hormone therapy on vaginal mucosal immunity

项目摘要/摘要 据估计，美国有100多万人认为自己是变性人。尽管最近 随着知名度的提高，跨性别者仍然被边缘化，并受到健康差距的影响，而且 在生物医学研究中的代表性不足。有充分的证据表明，变性人不成比例地 与他们的顺性同龄人相比，受艾滋病毒影响的人更多，但其基础尚不完全清楚。在……里面 特别是，我们对阴道粘膜免疫防御变化的了解非常有限。 接受慢性睾丸素治疗的变性人和变性人的间隔室 性别肯定激素疗法的一部分。这与了解变性人男子报告的艾滋病毒风险有关 异性恋、非异性恋和双性恋取向，使变性人与顺性人发生性关系 男性是一个独特且未被充分研究的群体.我们的中心假设是性别肯定激素疗法在 变性人导致先天免疫微环境失调和屏障功能受损 阴道粘膜间隙，增加了艾滋病毒在阴道穿透过程中传播的风险。的目标是 这个项目是用一种新的方法来描述交叉激素治疗对阴道间隔的影响。 商业上可以买到的重建的阴道组织模型已经被证明是激素反应的 并支持感染艾滋病毒。我们提出了三个目标来检验我们的假设。首先，我们将描述 睾丸激素占优势的阴道的组织学与雌二醇性阴道的对比，观察屏障 功能、粘蛋白表达和稳态细胞因子/趋化因子释放。睾丸素对人体健康的影响 还将检查乳酸菌的定植情况。接下来，我们将进行转录研究，以确定 睾丸激素优势阴道的基因表达谱识别免疫信号的变化 可能对宿主-病原体相互作用产生负面影响的途径。最后，我们将检查艾滋病毒感染在 比较睾丸激素主导的阴道和雌二醇刺激的阴道以确定艾滋病毒传播是否 增加了。在这个项目完成后，我们将对组织学和 睾酮对阴道隔膜的免疫学影响，识别防御弱点 阴道完整的变性人中残留的下女性生殖道会增加感染艾滋病毒的风险 变速箱。我们相信，我们的数据将有助于为正在经历 性别肯定荷尔蒙治疗，以减少艾滋病毒和其他性传播感染跨粘膜表面的风险。

PROJECT SUMMARY/ABSTRACT It is estimated that more than one million people in the United States identify as transgender. Despite recent increased visibility, transgender individuals remain marginalized and subject to health disparities, and are underrepresented in biomedical research. It is well documented that transgender persons are disproportionately affected by HIV compared to their cisgender counterparts, but the basis for this is incompletely understood. In particular, we have a very limited understanding of changes in mucosal immune defenses in the vaginal compartment in transgender men and transmasculine individuals who receive chronic testosterone therapy as part of gender affirming hormone therapy. This is relevant to understanding HIV risks as transgender men report heterosexual, non-heterosexual, and bisexual orientation, making transgender men who have sex with cisgender men a unique and understudied group. Our central hypothesis is that gender affirming hormone therapy in transgender men leads to a dysregulated innate immune microenvironment and impaired barrier function of the vaginal mucosal compartment, increasing the risk of HIV transmission during vaginal penetration. The goal of this project is to characterize the effects of cross hormone therapy on the vaginal compartment using a commercially available reconstructed vaginal tissue model that has been shown to be hormonally responsive and support infection with HIV. We propose three aims to test our hypothesis. First, we will characterize the histology of the testosterone dominant vagina in contrast to the estradiol primed vagina, looking at barrier function, mucin expression, and steady state cytokine/chemokine release. The effects of testosterone on colonization with lactobacillus will also be examined. Next, we will conduct transcriptomic studies to identify the gene expression profile of the testosterone dominant vagina to identify changes in the immunologic signaling pathways that could negatively impact host-pathogen interactions. Finally, we will examine HIV infection in the testosterone dominant vagina in comparison to the estradiol primed vagina to determine if HIV transmission is increased. At the completion of this project, we will have a broader understanding of the histologic and immunologic effects of testosterone on the vaginal compartment, identifying defensive weaknesses in the residual lower female genital tract in transgender men with an intact vagina that increase the risk of HIV transmission. We believe our data will help inform the development of strategies for individuals undergoing gender affirming hormone therapy to lessen the risk of HIV and other STI acquisition across this mucosal surface.