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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

基本信息

批准号：
10653080
负责人：
Patricia Silveyra
金额：
$ 52.65万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
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/10653080
关键词：
Accounting Adult Affect Agonist Air Movements Air Pollution Allergens Asthma Automobile Driving Award Binding Biological Cells Data Development Diagnosis Disease Disparity 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 Life Liquid substance Lung Lung diseases Measures Mediating Mediator Membrane Menstrual cycle Menstruation Modeling Molecular Morbidity - disease rate Mus National Heart, Lung, and Blood Institute Nuclear Outcome Pathway interactions Patients Phenotype Physiological Ploidies Population Prevalence Puberty Public Health Pulmonary Inflammation 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&apos s Health Women&apos s Role airway hyperresponsiveness airway obstruction antagonist asthma exacerbation asthma model asthma prevention asthmatic asthmatic patient 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

项目摘要

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.

摘要