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.

项目总结/文摘