Sex, Gender, and HIV Transmission: Defining the Impact of Biological Sex and Sex Hormones on Epithelial and Immune Cell Transcriptomics and HIV Transmission in Human Rectal Tissues

项目摘要/摘要 尽管变性人妇女和变性人男子感染艾滋病毒的负担不成比例地高， 在美国，在艾滋病毒预防研究中，性别少数群体的比例仍然偏低。虽然许多变性人 个体利用女性化和男性化荷尔蒙，在我们的机制中有关键的知识缺口 了解性别肯定激素治疗对直肠粘膜环境的影响 易受艾滋病毒感染的场所。这是最重要的，因为生物性和性激素 通过影响上皮细胞和免疫细胞的转录活性来调节其对上皮和免疫细胞功能的影响 这些作用可以改变直肠粘膜对艾滋病毒感染的易感性。的具体目标 这项建议旨在比较直肠粘膜免疫的性别特异性、空间定位的基因表达模式。 利用空间转录组学研究顺性男性和顺性女性之间的上皮细胞亚群 结合单细胞RNA测序(AIM 1)，确定直肠单细胞转录特征 体外性激素暴露后顺性男性和顺性别女性的粘膜细胞亚群 (目标2)，并使用HIV外植体挑战模型来检查体外性激素治疗的影响 关于直肠组织对艾滋病毒感染的易感性和宿主黏膜免疫反应(目标3)。这项研究 战略将促进为期5年的职业发展和培训计划，使格里姆斯利·阿克利博士能够 以她以前的研究经验为基础，获得关键的指导研究培训：1)生物信息学和 转录数据分析，2)粘膜免疫学和艾滋病毒传播，以及3)性行为和 基于性别的艾滋病毒研究。为了实现这些培训目标，格里姆斯利·艾克利博士组建了一个 拥有粘膜免疫学、性激素生物学、单细胞和 空间转录技术、基于性别和性别的研究以及生物统计学。这项提议将 利用埃默里大学强大的研究环境，并将得到现有资源的支持 通过埃默里疫苗中心的霍普诊所和埃默里国家灵长类研究中心。 格里姆斯利·阿克利博士的长期职业目标是领导一个成功和独立的翻译粘膜 专门研究基因组学应用和体外艾滋病毒外植体挑战的免疫学计划 模型，以更好地了解影响黏膜艾滋病毒易感性的生物和免疫因素 性别和性少数群体。这一长期目标的实现将通过 完成拟议的K23研究目标和培训计划，并获得高度支持 经验丰富的导师团队。这项提议将开始机械地解决生物性行为的影响。 以及性别肯定激素治疗对直肠粘膜环境和直肠HIV易感性的影响。数据 将作为未来NIH R级资金的基础，以促进格里姆斯利·阿克利博士的过渡 在艾滋病毒预防科学领域从事独立的临床-翻译研究生涯。

Project Summary/Abstract Despite a disproportionately high burden of HIV infection among transgender women and transgender men in the US, gender minorities remain underrepresented in HIV prevention research. While many transgender individuals utilize feminizing and masculinizing hormones, there are critical knowledge gaps in our mechanistic understanding of the effects of gender-affirming hormone therapy on the rectal mucosal environment, a critical site of vulnerability to HIV infection. This is of paramount importance, as biological sex and sex hormones mediate effects on epithelial and immune cell function through their influence on transcriptional activity of the cell, and these effects could alter the susceptibility of the rectal mucosa to HIV infection. The Specific Aims of this proposal are to compare sex-specific, spatially localized gene expression patterns of rectal mucosal immune and epithelial cell subpopulations between cisgender men and cisgender women utilizing spatial transcriptomics integrated with single cell RNA sequencing (Aim 1), to define the single cell transcriptomic signatures of rectal mucosal cellular subsets from cisgender men and cisgender women following ex vivo sex hormone exposure (Aim 2), and to use the HIV explant challenge model to examine the impact of ex vivo sex hormone treatment on rectal tissue susceptibility and host mucosal immune responses to HIV infection (Aim 3). This research strategy will facilitate a 5-year career development and training plan that will enable Dr. Grimsley Ackerley to build upon her prior research experience and gain critical mentored research training in: 1) Bioinformatics and Transcriptomic Data Analyses, 2) Mucosal Immunology and HIV transmission, and 3) the Conduct of Sex- and Gender-Based HIV Research. To achieve these training aims, Dr. Grimsley Ackerley has assembled a multidisciplinary mentorship team with expertise in mucosal immunology, sex hormone biology, single cell and spatial transcriptomic technologies, sex- and gender-based research, and biostatistics. This proposal will capitalize on a robust research environment at Emory University and will be supported by resources available through The Hope Clinic of the Emory Vaccine Center and the Emory National Primate Research Center. Dr. Grimsley Ackerley’s long-term career goal is to lead a successful and independent translational mucosal immunology program that specializes in the use of genomics applications and the ex vivo HIV explant challenge model to better understand biologic and immunologic factors that influence mucosal HIV susceptibility among gender and sexual minority populations. Achievement of this long-term goal will be made possible through the completion of the proposed K23 research aims and training plan, along with the support garnered from the highly experienced mentorship team. This proposal will begin to address, mechanistically, the effects of biological sex and gender-affirming hormone therapy on the rectal mucosal environment and rectal HIV susceptibility. The data generated will serve as the foundation for future NIH R-level funding to facilitate Dr. Grimsley Ackerley’s transition to an independent clinical-translational research career in the field of HIV prevention science.