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

项目总结/摘要 尽管2010年变性妇女和变性男子的艾滋病毒感染负担不成比例地高， 在美国，艾滋病预防研究中的性别少数群体人数仍然不足。虽然许多跨性别者 个人利用女性化和男性化激素，在我们的机械中存在关键的知识差距， 了解性别肯定激素治疗对直肠粘膜环境的影响， 易受艾滋病毒感染部位。这是至关重要的，因为生物性和性激素 介导上皮和免疫细胞功能的影响，通过其对转录活性的影响， 细胞，这些影响可能会改变直肠粘膜对HIV感染的易感性。的具体目标 本研究旨在比较直肠粘膜免疫组织化学中性别特异性、空间定位的基因表达模式， 和上皮细胞亚群之间的顺性男性和顺性女性利用空间转录组学 与单细胞RNA测序（Aim 1）相结合，以确定直肠癌的单细胞转录组特征， 在离体性激素暴露后来自顺性男性和顺性女性的粘膜细胞亚群 (Aim 2），并使用HIV外植体攻击模型来检查离体性激素治疗的影响 直肠组织易感性和宿主粘膜对HIV感染的免疫反应（目的3）。本研究 战略将促进5年的职业发展和培训计划，使格里姆斯利阿克利博士， 建立在她以前的研究经验，并获得关键的指导研究培训：1）生物信息学和 转录组学数据分析，2）粘液免疫学和HIV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，Grimsley Ackerley博士组织了一个 多学科导师团队，在粘膜免疫学，性激素生物学，单细胞和 空间转录组技术、基于性别的研究和生物统计。这项建议会 利用埃默里大学强大的研究环境，并将得到可用资源的支持 通过埃默里疫苗中心的希望诊所和埃默里国家灵长类动物研究中心。 博士Grimsley Ackerley的长期职业目标是领导一个成功和独立的翻译粘膜 免疫学计划，专门从事基因组学应用和体外HIV外植体挑战的使用 模型，以更好地了解影响粘膜HIV易感性的生物和免疫因素， 性别和性少数群体。要实现这一长期目标， 完成拟议的K23研究目标和培训计划，沿着的支持，从高度 经验丰富的导师团队。这个提议将开始从机制上解决生物性别的影响 以及性别确认激素治疗对直肠粘膜环境和直肠HIV易感性的影响。数据 产生的资金将作为未来NIH R级资金的基础，以促进Grimsley Ackerley博士的过渡 在艾滋病毒预防科学领域的独立临床转化研究生涯。

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.