Gonadal hormones as mediators of sex and gender influences in asthma

性腺激素作为性和性别影响哮喘的介质

• 批准号: 10308138
• 负责人: Patricia Silveyra
• 金额: $ 51.8万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308138
• 关键词: Accounting; Address; Adult; Affect; Agonist; Air Movements; Air Pollution; Allergens; Asthma; Automobile Driving; Award; Biological; Cells; Data; Development; Diagnosis; Disease; Environmental Exposure; Environmental Risk Factor; Epithelial Cells; Estradiol; Estrogen Receptors; Estrogens; Estrous Cycle; Experimental Models; Exposure to; Female; Feminization; Four Core Genotypes; Frequencies; Future; GPER gene; Gender; Gene Expression; Genes; Genomics; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Hospitalization; House mice; Human; Incidence; Individual; Individual Differences; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Knowledge; Laboratories; Lead; Life; Liquid substance; Lung; Lung Inflammation; Lung diseases; Measures; Mediating; Mediator of activation protein; Menstrual cycle; Menstruation; Modeling; Molecular; Morbidity - disease rate; Mus; National Heart, Lung, and Blood Institute; Nuclear; Nuclear Envelope; Outcome; Pathway interactions; Patients; Phenotype; Physiological; Ploidies; Population; Prevalence; Puberty; Public Health; Pyroglyphidae; Receptor Signaling; Recommendation; Recording of previous events; Reporting; Research; Research Priority; Respiratory Failure; Role; Severities; Sex Chromosomes; Sex Differences; Signal Transduction; Stimulus; Strategic Planning; Structure of parenchyma of lung; Symptoms; Testing; Therapeutic Agents; United States National Institutes of Health; Variant; Woman; Women' s Health; Women' s Role; airway hyperresponsiveness; airway obstruction; asthma exacerbation; asthma model; asthma prevention; asthmatic; asthmatic patient; base; bronchial epithelium; cis-female; cost; cytokine; differential expression; dosage; experimental study; female sex hormone; gender difference; gender disparity; hormone therapy; male; men; middle age; mortality; mouse model; non-genomic; novel therapeutics; personalized therapeutic; prevent; respiratory; response; sex; sex disparity; transgender; transgender women

ABSTRACT Asthma is a lung disease caused by exaggerated lung inflammation leading to airway obstruction and compromised airflow. Despite significant advances in its diagnosis and treatment, asthma continues to be a significant health problem affecting more than 25 million patients in the US, and over 300 million around the world. Well-characterized sex and gender differences in asthma have been reported, with changes in morbidity throughout life. Starting around puberty and peaking during mid-life, women have increased asthma prevalence and higher rates of asthma exacerbations than men. Causes of these disparities remain unclear; however, studies have shown that sex-specific inflammatory mechanisms controlled by hormones contribute to differences in airway reactivity in response to environmental stimuli. Despite this, experimental models of asthma have not explored the contributions of sex hormones to inflammatory mechanisms in the female and male lung, and no studies have explored the effects of feminizing hormone therapy with estrogen in the lungs of trans women. Prior studies from our laboratory using mouse models have reported sex differences and influences of the estrous cycle and circulating sex hormones in the inflammatory response to environmental exposures. Based on these findings, we hypothesized that female sex hormones, specifically estrogens, contribute to asthma phenotypes in the lung via activation of inflammatory mechanisms mediated by estrogen receptors. In the proposed study, we will test this hypothesis by determining the mechanisms by which estrogen mediates sex and gender influences in asthma. In Aim 1, we will determine the contributions of sex chromosome complement (XX vs. XY) vs. gonadal hormones in asthma phenotypes, by developing a mouse house dust mite (HDM) asthma model on the four core genotypes (FCG) model. In Aim 2, we will study the contributions of estrogens to HDM-induced asthma outcomes using male and female gonadectomized mice treated with estradiol, as well as bronchial epithelial cells from male and female healthy and asthma patients to exposed to HDM in the presence/absence of estrogen receptor agonists/antagonists. In Aim 3, we will determine the roles of nuclear (ER) and membrane- bound (GPER-1) estrogen receptors in estrogen-mediated mechanisms of inflammation in HDM-induced asthma, using ER and GPER1 knockout mice. Our studies will be the first to characterize estrogen-mediated mechanisms of inflammation in asthma phenotypes in the male and female lung, contributing to the characterization of sex- and gender-specific factors accounting for inter-individual differences, as well as the effects of feminizing hormone therapy in lung pathobiology. We expect that our studies would serve to develop potential sex- and gender-specific treatments and recommendations for dosage of therapeutic agents to treat and prevent asthma in cis and transgender women.

抽象的 哮喘是由夸张的肺部炎症引起的肺疾病，导致气道阻塞和 气流受损。尽管其诊断和治疗取得了重大进展，但哮喘仍然是 影响美国超过2500万患者的重大健康问题，周围有超过3亿 世界。据报道，哮喘的性别和性别差异良好，发病率变化 一生。从青春期开始，在中年时期，妇女增加了哮喘患病率 哮喘加重的发生率高于男性。这些差异的原因尚不清楚；然而， 研究表明，由激素控制的性别特异性炎症机制有助于差异 在响应环境刺激的气道反应性中。尽管如此，哮喘的实验模型尚未 探索了性激素对雌性和雄性肺炎症机制的贡献，没有 研究探索了雌激素在跨性别女性肺中用雌激素女性化的荷尔蒙治疗的影响。事先的 我们实验室使用小鼠模型的研究报告了性别差异和发情的影响 在对环境暴露的炎症反应中的循环和循环性激素。基于这些 调查结果，我们假设女性性激素，特别是雌激素，有助于哮喘表型 在肺中通过激活雌激素受体介导的炎症机制。在拟议的研究中 我们将通过确定雌激素介导性和性别的机制来检验这一假设 哮喘的影响。在AIM 1中，我们将确定性别染色体补体的贡献（XX与XY） 通过在哮喘表型中的性腺激素与性腺激素，通过在上面开发小鼠房屋尘螨（HDM）哮喘模型 四个核心基因型（FCG）模型。在AIM 2中，我们将研究雌激素对HDM诱导的贡献 使用雌二醇治疗的雄性和雌性性腺切除小鼠以及支气管 来自男性和女性健康和哮喘患者的上皮细胞在存在/不存在的情况下暴露于HDM 雌激素受体激动剂/拮抗剂。在AIM 3中，我们将确定核（ER）和膜的作用 在HDM诱导的雌激素介导的炎症机制中结合（GPER-1）雌激素受体 哮喘，使用ER和GPER1敲除小鼠。我们的研究将是第一个表征雌激素介导的 雄性和雌性肺中炎症机制 性别和性别特异性因素的表征，占个体间差异的特征 女性激素治疗在肺病理生物学中的影响。我们希望我们的研究将有助于发展 潜在的性别和性别特异性治疗以及治疗剂量的建议 并预防顺式和变性妇女的哮喘。