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.

项目概要/摘要 据估计，美国有超过一百万人被认定为跨性别者。尽管最近 随着知名度的提高，跨性别者仍然被边缘化并受到健康差异的影响，并且 在生物医学研究中代表性不足。有充分证据表明跨性别者比例过高 与同性别者相比，他们受到艾滋病毒的影响，但其基础尚不完全清楚。在 特别是，我们对阴道粘膜免疫防御变化的了解非常有限 接受慢性睾酮治疗的跨性别男性和跨男性个体的隔室 性别肯定激素疗法的一部分。这与了解跨性别男性报告的艾滋病毒风险有关 异性恋、非异性恋和双性恋取向，使得与顺性别发生性关系的跨性别男性 男性是一个独特且未被充分研究的群体。我们的中心假设是性别肯定激素疗法 跨性别男性会导致先天免疫微环境失调和屏障功能受损 阴道粘膜区，增加了阴道插入过程中艾滋病毒传播的风险。目标是 该项目旨在利用交叉激素疗法来表征交叉激素疗法对阴道室的影响 市售的重建阴道组织模型已被证明具有激素反应性 并支持艾滋病毒感染。我们提出三个目标来检验我们的假设。首先，我们将表征 睾酮主导阴道与雌二醇引发阴道的组织学对比，观察屏障 功能、粘蛋白表达和稳态细胞因子/趋化因子释放。睾酮对身体的影响 还将检查乳酸菌的定植。接下来，我们将进行转录组研究来鉴定 睾酮主导阴道的基因表达谱，以确定免疫信号的变化 可能对宿主与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情况 将睾酮主导的阴道与雌二醇引发的阴道进行比较，以确定 HIV 传播是否有效 增加。该项目完成后，我们将对组织学和 睾酮对阴道室的免疫作用，识别阴道室的防御弱点 阴道完整的跨性别男性残留的下女性生殖道会增加感染艾滋病毒的风险 传播。我们相信我们的数据将有助于为正在接受治疗的个人制定策略提供信息 性别肯定激素疗法可降低粘膜表面感染艾滋病毒和其他性传播感染的风险。