Gender and Asthma

性别与哮喘

基本信息

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
项目类别：
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

项目摘要

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.

抽象的哮喘对男孩的影响比女孩更大，但是性别开关发生在青春期和哮喘之后发生的性别开关更为普遍女人比男人。该研究提案调查了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和生物学途径的差异严重的哮喘。我们对特征性哮喘同胞和大数据库的良好特征分析表明，严重哮喘在年轻男孩和中年女性中表现出双峰峰[3]，指向性激素哮喘严重程度的机制。 SARP 1-3的女性性激素水平的初步数据（2001-2018）表明，FEV1（％）与雌二醇呈负相关，但与孕激素呈正相关。另外，肾上腺雄激素脱氢 - 雌激素硫酸盐（DHEA-S）与FEV1正相关（％）男性和男性，但睾丸激素水平与男性的FEV1（％）相关，而女性则无关。我们的数据也是如此表明性激素通过对性类固醇受体（SSR）的影响调节气道炎症。来自128 SARP 3参与者支气管镜检查获得的支气管上皮细胞的基因表达数据与哮喘相关的雌激素受体1和2（ESR1和ESR2）基因之间的显着相关性表达和炎性细胞因子受体（IL6R，IL4R，IL5RA和IL13RA1）基因表达。我们的 SARP1-2 BEC微阵列数据（n = 72名女性，32名男性）的初步分析显示性别特异性差异 - 靶向代表特定生物学功能的相互作用基因组（线粒体功能男性中的女性和干扰素信号）。这些数据表明性和性激素起着重要作用在哮喘遗传风险变异的临床表现中。基于这些累积发现，我们假设性别和性激素会影响免疫系统激活和气道炎症以驱动哮喘整个生命周期中男性和女性的表型和进展有所不同。在目标1中，我们评估了如何性激素血清浓度和SSR在血液，上和下气道细胞中的表达决定T2 男性和女人的炎症和哮喘严重程度。在AIM 2中，我们确定基因座的性别特异性遗传效应 DNA变异与激素和核能相互作用引起的哮喘风险和严重程度的基因组跨越基因组受体表达。在AIM 3中，我们将评估哮喘的性二态性是否与高阶有关基因相互作用和基因调节网络中性别特异性构型的变化。提议研究有可能定义关键的激素和基因组驱动因素的哮喘风险和严重程度男性和女人的寿命，并解决了关于性别和性激素如何改变哮喘的巨大知识差距风险和严重性。未来的研究将使用这些数据来识别个性化的基于激素的风险男性和女人的分层和治疗方法，无论背景祖先如何。