Understanding the effects of Gender Affirming Hormone Therapy (GAHT) on immune function using a systems immunology approach

使用系统免疫学方法了解性别肯定激素疗法 (GAHT) 对免疫功能的影响

• 批准号: 10749957
• 负责人: Boris Novakovic
• 金额: $ 15.14万
• 依托单位: MURDOCH CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-22 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749957
• 关键词: ATAC-seq; Address; Affect; Antibodies; B-Lymphocytes; Biological Assay; Blood; Blood Cells; Blood specimen; CD28 gene; CD3 Antigens; Cell physiology; Cells; Cheek structure; Cholesterol; Chromatin; Chronic; Circulation; Cohort Studies; Collection; DNA Methylation; Environment; Epigenetic Process; Epithelial Cells; Estradiol; Exposure to; Feces; Feminization; Flow Cytometry; Fumarates; Gender Identity; Gene Expression; Gonadal Steroid Hormones; HIV; HIV Infections; Hair; Histones; Hydrocortisone; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunology; Immunophenotyping; In Vitro; Individual; Infection; Inflammation; Knowledge; Ligands; Link; Longitudinal cohort; Maps; Masculine; Measures; Metabolic; Microbe; Modeling; Molecular; Molecular Biology; Molecular Profiling; Natural Killer Cells; Nuclear Receptors; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Population; Predisposition; Pregnancy; Prevalence; Puberty; Public Health; Risk; Role; Saliva; Sex Differences; Sexual Transmission; Sexually Transmitted Diseases; Signal Pathway; Stress; System; T cell response; T-Cell Proliferation; T-Lymphocyte; Techniques; Testosterone; Therapeutic; Therapeutic Intervention; Training; United States; Vaccines; Viral; Virus; Virus Diseases; cell type; circulating biomarkers; cis-female; cohort; cytokine; epigenomics; fecal microbiota; fighting; gender affirming hormone therapy; genomic locus; high dimensionality; histone modification; immune function; immunoregulation; improved; in vitro Model; innate immune function; microbial; microbiome; monocyte; peripheral blood; predicting response; receptor; recruit; reproductive tract; response; sample collection; sex assigned at birth; sexual dimorphism; single-cell RNA sequencing; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; transgender; transgender men; transgender women; vaginal microbiota

PROJECT SUMMARY One million individuals in the United States identify as transgender (0.39% of population), of which 90% are either on gender-affirming hormone therapy (GAHT) or considering starting GAHT. Understanding how feminizing GAHT (estradiol) and masculinizing GAHT (testosterone) influence immune function is imperative, considering that (i) transgender women have a significantly increased prevalence of Human Immunodeficiency Virus (HIV) infection worldwide and (ii) little is known about how GAHT influences immune function or susceptibility to infections. To address this gap in knowledge, our team will combine established state-of-the-art systems immunology approaches to a completed longitudinal cohort of transgender women before and during GAHT. We previously used this longitudinal model to show that both feminizing and masculinizing GAHT induced DNA methylation changes at specific genomic loci in whole peripheral blood, some of which were previously associated with puberty or pregnancy. In the first three aims of this project, we will use viably stored peripheral blood mononuclear cells from transgender women at baseline, and 3 and 6 months following GAHT. By applying a systems immunology approach, we first seek to establish how GAHT changes the circulating immune profile and plasma metabolites, both of which are predictors of response to infection and vaccines. Next, innate, and adaptive immune function will be assessed through in vitro stimulation with a range of microbial and viral microbes, specifically HIV, followed by cytokine assays. Finally, in Aim 3 we will map the underlying epigenomic profile of specific immune cell types, by profiling active histone modifications and open chromatin at single cell level. Together, the above approach will identify the key molecular drivers of altered immune function in response to GAHT and generate new hypotheses for further study. Ultimately, understanding how GAHT alters the molecular biology of immune cells will open new avenues to therapeutic intervention in cases where immune function is compromised because of GAHT. In aim 4, we will use our established longitudinal GAHT recruitment strategy to establish a cohort of transgender individuals with extensive biospecimen collection. This will allow us to explore the effects of GAHT on the vaginal and fecal microbiota and stress, which are known modulators of immunity. Once established, this longitudinal cohort will provide opportunities to apply a range of state-of-the-art molecular and immunophenotyping techniques to understand if and how GAHT affects susceptibility to HIV infection.

项目概要 美国有 100 万人被认定为跨性别者（占人口的 0.39%），其中 90% 是跨性别者 正在接受性别肯定激素疗法 (GAHT) 或考虑开始 GAHT。了解如何 女性化 GAHT（雌二醇）和男性化 GAHT（睾酮）对免疫功能的影响势在必行， 考虑到 (i) 跨性别女性的人体免疫缺陷患病率显着增加 全球范围内的病毒 (HIV) 感染，以及 (ii) 人们对 GAHT 如何影响免疫功能或了解甚少 易受感染。 为了解决这一知识差距，我们的团队将结合现有的最先进的系统免疫学 在 GAHT 之前和期间对跨性别女性的完整纵向队列进行研究。我们之前 使用这个纵向模型表明女性化和男性化 GAHT 都会诱导 DNA 甲基化 全外周血中特定基因组位点的变化，其中一些以前与 青春期或怀孕。 在该项目的前三个目标中，我们将使用来自以下来源的存活的外周血单核细胞： 跨性别女性在基线以及 GAHT 后 3 个月和 6 个月。通过应用系统免疫学 方法，我们首先寻求确定 GAHT 如何改变循环免疫特征和血浆代谢物， 两者都是对感染和疫苗反应的预测因子。接下来，先天性和适应性免疫功能 将通过一系列微生物和病毒微生物（特别是艾滋病毒）的体外刺激进行评估， 随后进行细胞因子测定。最后，在目标 3 中，我们将绘制特异性免疫的潜在表观基因组图谱。 通过在单细胞水平分析活性组蛋白修饰和开放染色质来分析细胞类型。综上所述， 该方法将确定 GAHT 导致免疫功能改变的关键分子驱动因素，并生成 进一步研究的新假设。最终，了解 GAHT 如何改变免疫的分子生物学 在免疫功能受损的情况下，细胞将为治疗干预开辟新途径 因为GAHT。 在目标 4 中，我们将使用我们既定的纵向 GAHT 招募策略来建立一个跨性别者队列 拥有广泛生物样本收集的个人。这将使我们能够探索 GAHT 对阴道的影响 粪便微生物群和压力是已知的免疫调节剂。一旦建立，这个纵向 该队列将提供应用一系列最先进的分子和免疫表型分析的机会 技术来了解 GAHT 是否以及如何影响 HIV 感染的易感性。