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

了解跨性别激素治疗对阴道粘膜免疫的影响

• 批准号: 10749174
• 负责人: Robin R Ingalls
• 金额: $ 26.7万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-14 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749174
• 关键词: 3-Dimensional; Adult; Affect; Anal Sex; Area; Basic Science; Biological Assay; Biomedical Research; Bisexual; Boston; Cells; Chronic; Communities; DNA Sequencing Facility; Data; Development; Estradiol; Female; Female genitalia; Gene Expression; Gene Expression Profile; Genital; Genitalia; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; HIV risk; HIV-1; Health; Healthcare; Heterosexuals; Histologic; Histology; Hormonal; Human immunodeficiency virus test; Immune; Immune response; Immune signaling; Immunologics; Immunology; Impairment; Individual; Infection; Knowledge; Laboratories; Lactobacillus; Ligands; Masculine; Medical; Meta-Analysis; Michigan; Modeling; Mucins; Mucosal Immunity; Mucous Membrane; Organism; Penetration; Persons; Physiology; Poly I-C; Prevalence; Regimen; Reporting; Research Personnel; Research Priority; Residual state; Risk; Risk Factors; Role; Sex Orientation; Sexual Reassignment; Sexually Transmitted Diseases; Signal Pathway; Sterility; Surface; Testing; Testosterone; Thick; Tissue Model; Tissues; United States; United States National Institutes of Health; Universities; Vagina; Work; assigned female at birth; chemokine; cis-male; cisgender; cultural competence; cytokine; female sex hormone; gender affirming hormone therapy; health disparity; hormone therapy; interest; male sex hormones; marginalization; microbial; non-heterosexual; pathogen; reproductive tract; response; screening; sex; sexual risk behavior; substance use; transcriptomics; transgender; transgender men; transgender women; transmasculine; transmission process; tumor-immune system interactions; vaginal microbiome; vaginal mucosa

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.

项目摘要/摘要 据估计，美国有超过一百万的人被认为是变性者。尽管最近 可见性提高，跨性别者仍然处于边缘地位并存在健康差异，并且是 生物医学研究的代表性不足。有充分的文献证明，跨性别人士不成比例 受艾滋病毒的影响与他们的cisgender对应物相比，这是不完全理解的。在 特别是，我们对阴道中粘膜免疫防御的变化的理解非常有限 接受慢性睾丸激素治疗的变性男性和跨性别者的隔室 性别确认激素治疗的一部分。这与理解艾滋病毒风险作为变性人报告有关 异性恋，非异性恋和双性恋取向，使跨性别男人与sisgender发生性关系 男人是一个独特而研究的群体。我们的中心假设是性别确认激素治疗 跨性别男性导致先天性免疫微环境失调，障碍功能受损 阴道粘膜室，增加了阴道渗透过程中HIV传播的风险。目标 该项目是为了表征使用跨激素治疗对阴道室的影响 已证明具有荷尔蒙反应性的市售重建阴道组织模型 并支持艾滋病毒感染。我们提出了三个旨在检验假设的目标。首先，我们将表征 睾丸激素主导阴道的组织学与雌二醇底漆的阴道相反，看着屏障 功能，粘蛋白表达和稳态细胞因子/趋化因子释放。睾丸激素对 还将检查与乳杆菌的定殖。接下来，我们将进行转录组学研究，以确定 睾丸激素显性阴道的基因表达谱，以鉴定免疫信号的变化 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 与雌二醇的阴道相比，睾丸激素显着的阴道显着性阴道，以确定HIV传播是否为 增加。该项目完成时，我们将对组织学和 睾丸激素对阴道室的免疫学影响，鉴定出防御性弱点 残留的较低的女性生殖道在具有完整阴道的变性男性中，增加了艾滋病毒的风险 传播。我们认为我们的数据将有助于为正在进行的个人制定策略 性别确认激素治疗，以减少粘膜表面上艾滋病毒和其他性传染的风险。