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

性、性别和 HIV 传播：定义生物性别和性激素对人类直肠组织中上皮细胞和免疫细胞转录组学以及 HIV 传播的影响

• 批准号: 10700594
• 负责人: Cassie Grimsley Ackerley
• 金额: $ 17.23万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700594
• 关键词: AIDS prevention; Achievement; Address; Anal Sex; Androgens; Anti-Inflammatory Agents; Antigen-Presenting Cells; Attention; B-Cell Activation; B-Lymphocytes; Bioinformatics; Biological; Biological Assay; Biological Factors; Biological Response Modifiers; Biology; Biology of HIV Transmission; Biometry; Biopsy; CXCL10 gene; CXCR3 gene; Cell Proliferation; Cell physiology; Cells; Chromosome Mapping; Clinic; Colon; Data; Data Analyses; Development; Effectiveness; Environment; Epithelial Cells; Epithelium; Estrogen Therapy; Estrogens; Event; Exposure to; Feminization; Foundations; Funding; Future; Gender; Gene Expression; Gene Expression Profile; Gene Expression Regulation; General Population; Genes; Genetic; Genetic Transcription; Genomics; Goals; Gonadal Steroid Hormones; Gut Mucosa; HIV; HIV Infections; HIV Seronegativity; Hormone use; Hormones; Human; Immune; Immune response; Immunologic Factors; Immunologics; Immunology; Individual; Inflammatory; Influentials; Interferon Type II; Interleukin-10; Interleukin-2; Interleukin-6; Knowledge; Left; Mediating; Mentors; Mentorship; Methodology; Modality; Modeling; Mucins; Mucosal Immune Responses; Mucositis; Mucous Membrane; Mucous body substance; Natural Killer Cells; Pathway interactions; Persons; Pilot Projects; Population; Predisposition; Prevention Research; Primates; Public Health; Rectum; Research; Research Training; Resolution; Resources; Risk; Science; Sex Chromosomes; Sex Differences; Sexual and Gender Minorities; Site; T-Lymphocyte; Techniques; Technology; Testosterone; Tissues; Training; Translational Research; United States National Institutes of Health; Universities; Up-Regulation; Vaccines; Virus Replication; biological sex; career; career development; cis-female; cis-male; clinical translation; cytokine; epithelial repair; epithelial stem cell; experience; experimental study; fortification; gastrointestinal epithelium; gender affirming hormone therapy; gender affirming hormones; gender minority; gene repression; hormone therapy; immune activation; improved; innovation; men who have sex with men; multidisciplinary; pre-exposure prophylaxis; preventive intervention; programs; receptor; rectal; rectal HIV transmission; research study; response; sex; sexual minority group; single-cell RNA sequencing; therapeutic development; therapeutic target; transcriptome; transcriptomics; transgender; transgender men; transgender women; transmission process; vaccine response

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.

项目摘要/摘要 尽管跨性别妇女和变性男性在 在艾滋病毒预防研究中，美国的性别少数群体的人数不足。而许多变性者 个人利用女性化和男性化的激素，我们的机理存在关键的知识差距 了解性别疗法的马龙治疗对直肠粘膜环境的影响，这是一个关键 艾滋病毒感染的脆弱性部位。这至关重要，因为生物学性爱和性恐怖 通过对上皮和免疫功能作用的影响，通过其对转录活性的影响 细胞，这些作用可能会改变直肠粘膜对HIV感染的敏感性。具体目的 该建议是比较直肠粘膜免疫的性别特异性，空间局部的基因表达模式 顺式男性和赋予人的女性利用空间转录组学之间的上皮细胞亚群 与单细胞RNA测序集成（AIM 1），以定义直肠的单细胞转录组特征 在体内性激素暴露后，来自sisgender男性和顺性妇女的粘膜细胞子集 （AIM 2），并使用HIV Explant挑战模型来检查体内性骑马治疗的影响 关于直肠组织敏感性和对HIV感染的宿主粘膜免疫反应（AIM 3）。这项研究 策略将促进一项为期5年的职业发展和培训计划，该计划将使Grimsley Ackerley博士能够 在她先前的研究经验的基础上，并获得了至关重要的研究培训：1）生物信息学和 转录组数据分析，2）粘膜免疫学和HIV传播，以及3）性行为和性别的行为 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·阿克利（Grimsley Ackerley）博士组装了 多学科心态团队具有粘膜免疫学，性激素生物学，单细胞和单细胞和 空间转录技术，基于性别和性别的研究以及生物统计学。该提议将 利用埃默里大学（Emory University）的强大研究环境，并将获得可用资源的支持 通过埃默里疫苗中心和埃默里国家灵长类动物研究中心的希望诊所。 格里姆斯利·阿克利（Grimsley Ackerley）博士的长期职业目标是领导成功且独立的翻译粘膜 专门从事基因组应用和体内HIV Epplant挑战的免疫学计划 更好地了解影响粘膜HIV易感性的生物学和免疫学因素的模型 性别和性少数群体。实现这一长期目标将通过 拟议的K23研究目标和培训计划的完成，以及从高度的支持中获得的支持 经验丰富的精神训练团队。该建议将开始机械地解决生物性别的影响 在直肠粘膜环境和直肠HIV易感性上进行性别疗法治疗。数据 生成的将成为未来NIH R级资助的基础，以促进格里姆斯利·阿克利（Grimsley Ackerley）的过渡 从事艾滋病毒预防科学领域的独立临床翻译研究职业。