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.

项目总结 美国有100万人认为自己是变性人(占总人口的0.39%)，其中90%是变性人 要么接受性别肯定激素治疗(GAHT)，要么考虑开始GAHT。了解如何 使GAHT(雌二醇)女性化和GAHT(睾酮)男性化影响免疫功能是势在必行的， 考虑到(一)变性人妇女的人类免疫缺陷患病率显著增加 全球范围内的病毒(HIV)感染和(Ii)关于GAHT如何影响免疫功能或 对感染的敏感性。 为了解决这一知识差距，我们的团队将结合已建立的最先进的免疫学系统 在伽玛刀治疗前和治疗中对变性妇女进行完整纵向队列的方法。我们之前 使用这个纵向模型来证明女性化和男性化GAHT都能诱导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。 在这个项目的前三个目标中，我们将使用可视存储的来自 变性人女性在基线，以及GAHT后3个月和6个月。通过应用系统免疫学 首先，我们试图确定GAHT如何改变循环免疫状况和血浆代谢物， 这两者都是对感染和疫苗反应的预测因子。其次，先天免疫和获得性免疫功能 将通过一系列微生物和病毒微生物的体外刺激进行评估，特别是艾滋病毒， 然后进行细胞因子分析。最后，在目标3中，我们将绘制特定免疫的潜在表观基因组图谱 细胞类型，通过在单细胞水平上分析活性的组蛋白修饰和开放的染色质。总而言之，以上 该方法将确定免疫功能改变的关键分子驱动因素，以响应GAHT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 细胞将为免疫功能受损的病例的治疗干预开辟新的途径 因为GAHT的缘故。 在目标4中，我们将使用我们既定的纵向GAHT招募战略来建立一个变性人队列 拥有大量生物标本收藏的个人。这将使我们能够探索GAHT对阴道的影响 以及粪便微生物区系和压力，它们是已知的免疫调节器。一旦确立，这一纵向 队列将提供应用一系列最先进的分子和免疫表型鉴定的机会 了解GAHT是否以及如何影响艾滋病毒感染易感性的技术。