Gender and Asthma

性别与哮喘

• 批准号: 10583660
• 负责人: Joe Zein
• 金额: $ 41.91万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2023-06-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10583660
• 关键词: Address; Adrenal Glands; Adult; Affect; African American population; Allergic inflammation; Androgens; Asthma; Attenuated; Binding; Biological; Biological Markers; Biological Process; Blood; Bronchoscopy; Cells; Classification; Clinical; Coupled; Cytokine Receptors; DNA; Data; Databases; Dehydroepiandrosterone Sulfate; Development; Disease; ESR1 gene; ESR2 gene; Elements; Enrollment; Epithelial Cells; Estradiol; Estrogens; Excision; Exhibits; Female; Future; Gender; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Order; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genomics; Goals; Gonadal Steroid Hormones; Hormonal; Hormone Receptor; Hormones; IL13RA1 gene; IL17 gene; IL4R gene; IL5RA gene; Immune; Immune system; Inflammation; Inflammatory; Interferons; Intervention; Knowledge; Longevity; Lung diseases; Maps; Measures; Micro Array Data; Mitochondria; Modality; Multiomic Data; National Heart, Lung, and Blood Institute; Not Hispanic or Latino; Nuclear Receptors; Outcome; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Perimenopause; Persons; Phenotype; Play; Population; Prevalence; Production; Progesterone; Progesterone Receptors; Proteins; Puberty; Pulmonary Function Test/Forced Expiratory Volume 1; Regulation; Research; Research Proposals; Risk; Role; Same-sex; Serum; Severities; Sex Differences; Signal Transduction; Sputum; Steroid Receptors; Systems Biology; Testing; Testosterone; Variant; Woman; admixture mapping; airway inflammation; airway obstruction; biobank; boys; bronchial epithelium; caucasian American; clinical phenotype; clinically actionable; cohort; endophenotype; follow-up; gene interaction; gene regulatory network; genetic variant; genome sequencing; genome wide association study; genome-wide; girls; human interactome; male; member; men; middle age; molecular phenotype; multiple omics; novel; precision medicine; programs; protein protein interaction; pulmonary function; receptor expression; risk stratification; risk variant; sex; sexual dimorphism; transcriptome sequencing; whole genome

Abstract Asthma affects boys more than girls, but gender-switch occurs after puberty and asthma is more common in women than men. This research proposal investigates the effect of sex and sex hormones on asthma severity. The long-term goal of our studies is to identify sex related differences in genetic risks and biological pathways of severe asthma. Our analyses of well characterized asthma cohorts and large databases reveal that severe asthma exhibits a bimodal peak in young boys and middle age women [3], which pointes to sex hormones in mechanisms of asthma severity. Preliminary data of sex hormone levels from women enrolled in SARP 1-3 (2001-2018) showed that FEV1 (%) correlated negatively with estradiol, but positively with progesterone. Additionally, the adrenal androgen dehydro-epiandrosterone sulfate (DHEA-S) correlated positively with FEV1 (%) in women and men, but testosterone levels correlated with FEV1 (%) in men but not in women. Our data also suggest that sex hormones modulate airway inflammation through their effect on sex steroids receptors (SSRs). Gene expression data from bronchial epithelial cells obtained by bronchoscopy from 128 SARP 3 participants with asthma revealed significant correlation between estrogen receptors 1 and 2 (ESR1 and ESR2) gene expression and inflammatory cytokine receptors (IL6R, IL4R, IL5RA, and IL13RA1) gene expression. Our preliminary analyses of SARP1-2 BEC microarray data (n= 72 women, 32 men) showed sex-specific differential- targeting of groups of interacting genes representing particular biological functions (mitochondrial function in women and interferon signaling in men). These data suggest that sex and sex hormones play an important role in the clinical manifestations of asthma genetic risk variants. Based on these cumulative findings, we hypothesize that sex and sex hormones influence immune system activation and airway inflammation to drive asthma phenotypes and progression differentially in males and females across the lifespan. In aim 1 we evaluate how sex hormone serum concentrations and SSRs expression in blood, upper, and lower airway cells determine T2 inflammation and asthma severity in men and women. In aim 2 we identify the sex-specific genetic effects of loci across the genome on asthma risk and severity resulting from DNA variant interactions with hormone and nuclear receptor expression. In aim 3, we will assess whether sexual dimorphism of asthma is related to a higher order of gene interactions and variation in sex-specific configurations in gene regulatory networks. The proposed studies have the potential to define key hormonal and genomic drivers of asthma risk and severity over the lifespan in men and women and address a large knowledge gap of how sex and sex hormones modify asthma risk and severity. Future studies will aim, using this data, to identify personalized, hormone-based risk stratification and treatment approaches in men and women, irrespective of background ancestry.

摘要 哮喘对男孩的影响比女孩大，但性别转换发生在青春期之后，哮喘在成年人中更常见。 女人比男人多。这项研究计划调查性和性激素对哮喘严重程度的影响。 我们研究的长期目标是确定与性别相关的遗传风险差异和生物学途径， 严重哮喘我们对特征明确的哮喘队列和大型数据库的分析显示， 哮喘在年轻男孩和中年妇女中表现出双峰峰[3]，这表明性激素在 哮喘严重程度的机制。参加SARP 1-3的妇女的性激素水平的初步数据 （2001-2018年）结果显示，FEV 1（%）与雌二醇呈负相关，与孕酮呈正相关。 此外，肾上腺雄激素硫酸脱氢表雄酮（DHEA-S）与FEV 1呈正相关 （%），但男性睾酮水平与FEV 1（%）相关，而女性睾酮水平与FEV 1（%）无关。我们的数据还 提示性激素通过其对性类固醇受体（SSRs）作用调节气道炎症。 通过支气管镜检查从128名SARP 3参与者获得的支气管上皮细胞的基因表达数据 雌激素受体1和2（ESR 1和ESR 2）基因与哮喘发病相关 表达和炎性细胞因子受体（IL 6 R、IL 4 R、IL 5 RA和IL 13 RA 1）基因表达。我们 SARP 1 -2 BEC微阵列数据的初步分析（n= 72名女性，32名男性）显示性别特异性差异- 靶向代表特定生物学功能（线粒体功能， 女性和男性中的干扰素信号传导）。这些数据表明，性和性激素发挥了重要作用 哮喘遗传风险变异的临床表现。基于这些累积的发现，我们假设 性和性激素影响免疫系统激活和气道炎症从而导致哮喘 表型和进展在男性和女性的整个生命周期的差异。在目标1中，我们评估如何 血清性激素浓度和血液、上下呼吸道细胞中的SSRs表达决定T2 炎症和哮喘的严重程度。在目标2中，我们确定了基因座的性别特异性遗传效应 在基因组中对哮喘风险和严重程度的影响，这是由于DNA变异与激素和核 受体表达在目标3中，我们将评估哮喘的性二型性是否与更高的阶相关 基因调控网络中性别特异性构型的基因相互作用和变异。拟议 研究有可能确定哮喘风险和严重程度的关键激素和基因组驱动因素， 并解决性和性激素如何改变哮喘的巨大知识缺口 风险和严重性。未来的研究将利用这些数据来确定个性化的、基于风险的风险。 分层和治疗方法，无论背景血统如何。