Androgen signaling in asthma

哮喘中的雄激素信号传导

基本信息

批准号：
10457998
负责人：
Tim Lahm
金额：
$ 38.3万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10457998
关键词：
Adrenal Cortex Hormones Androgen Receptor Androgen Therapy Androgens Asthma Attenuated Biology Characteristics Clinical Cross-Over Trials Data Dehydroepiandrosterone Sulfate Disease Double-Blind Method Drug Kinetics Enzymes Epithelial Cells Exhalation Exhibits Female Gene Expression Genes Genetic Variation Genotype Gonadal Steroid Hormones Hormones Human Hydroxysteroid Dehydrogenases Inflammation Inflammation Mediators Inflammatory Interleukin-13 Interleukin-4 Interleukin-5 Interleukin-6 Knowledge Lead Link Lung diseases Mediating Messenger RNA Nitric Oxide Outcome Pathway interactions Patients Peripheral Pilot Projects Placebo Control Plasma Population Positioning Attribute Prevalence Pulmonary Function Test/Forced Expiratory Volume 1 Randomized Regulation Research Role S-Nitrosothiols Serum Signal Transduction Smooth Muscle Myocytes Suggestion Symptoms Testing Testosterone Tissues United States National Institutes of Health Variant Woman airway epithelium airway obstruction asthmatic asthmatic patient base cell injury clinically relevant cohort cytokine dehydroepiandrosterone experience improved innovation male men new therapeutic target novel patient population precision medicine programs protein expression pulmonary function receptor expression respiratory smooth muscle response sex sexual dimorphism treatment response

项目摘要

PROJECT SUMMARY/ABSTRACT Asthma is a sexually dimorphic disease, with women exhibiting higher asthma prevalence and more severe manifestations than men. Projects 3 builds upon the rationale that androgens such as testosterone and dehydroepiandrosterone (DHEA) have been linked to better outcomes in asthma. However, mechanisms of androgen-mediated regulation of airway biology are only incompletely understood. In addition, it is unclear if androgen therapy is beneficial in severe asthma and if specific patient populations exist that could be targeted via a precision medicine approach. Project 3 aims to fill this knowledge gap and identify novel, therapeutically targetable mechanisms of androgen-mediated improvement in lung function. Ultimately, this will lead to novel, targeted and corticosteroid-sparing therapies for patients with severe asthma of either sex. We have generated intriguing new data suggesting a causal relationship between androgens and relief of human asthmatic airflow obstruction. In particular, we found that in women with mild asthma and low DHEA-sulfate plasma levels, DHEA treatment was associated with a significant improvement in FEV1. Second, we discovered in a cohort of severe asthma patients that a variant in position 1245 of the gene HSD3B1 (encoding an enzyme that increases tissue androgen levels) is associated with a lower FEV1 if DHEA-S plasma levels are low. Third, we found that increased androgen receptor mRNA abundance in airway epithelial cells (AECs) is associated with improved lung function and fewer asthma symptoms. These data led us to hypothesize that androgens exert beneficial effects on S- nitrosylation, pH regulation and inflammatory signaling that lead to improved lung function in patients with severe asthma, and that genetic variations in androgen signaling are clinically relevant modifiers of the therapeutic response in these patients. We propose the following specific aims: 1) To determine whether androgens favorably impact S-nitrosylation and pH regulation in brushed AECs from patients with severe asthma; 2) To study if androgens regulate pro-inflammatory mediator gene and protein expression in AECs from patients with severe asthma; and 3) To investigate if DHEA improves FEV1 and decreases FeNO in asthma patients with low DHEA-S levels and a favorable HSD3B1 genotype. The proposed studies are significant, since they will provide a better understanding of the yet unknown mechanisms and targets of androgen signaling in severe asthma. Conceptual innovation is provided at several levels: First, we will identify novel mechanisms of androgen signaling in AECs in severe asthma and establish a critical crosstalk with nitrosylation/de-nitrosylation, pH regulation and inflammation. Second, we will identify sex and androgens as modifiers of AEC-ASMC crosstalk. Third, we will perform the first mechanistic studies of the role of HSD3B1 in severe asthma. Upon conclusion of our studies, we will have identified novel and therapeutically targetable mechanisms of androgen signaling in AECs and ASMCs in severe asthma, and we will have identified a novel population of male and female patients that will benefit from a personalized and targeted hormone-based treatment approach.

项目概要/摘要哮喘是一种性别二态性疾病，女性哮喘患病率更高且病情更严重表现不如男性。项目 3 建立在以下基本原理之上：睾酮和睾酮等雄激素脱氢表雄酮（DHEA）与更好的哮喘治疗效果有关。然而，机制雄激素介导的气道生物学调节尚不完全清楚。此外，尚不清楚是否雄激素治疗对严重哮喘有益，如果存在可以针对的特定患者群体通过精准医学方法。项目 3 旨在填补这一知识空白并确定新颖的治疗方法雄激素介导的肺功能改善的靶向机制。最终，这将导致小说，对任一性别的严重哮喘患者进行靶向且少用皮质类固醇的治疗。我们已经生成了有趣的新数据表明雄激素与缓解人类哮喘气流之间存在因果关系梗阻。特别是，我们发现在患有轻度哮喘且 DHEA 硫酸盐血浆水平较低的女性中，DHEA 治疗与 FEV1 显着改善相关。其次，我们在一组重症患者中发现哮喘患者发现 HSD3B1 基因（编码一种酶，可增加组织如果 DHEA-S 血浆水平较低，雄激素水平）与较低的 FEV1 相关。第三，我们发现增加了气道上皮细胞 (AEC) 中雄激素受体 mRNA 丰度与肺功能改善相关以及更少的哮喘症状。这些数据使我们推测雄激素对 S-发挥有益作用亚硝基化、pH 调节和炎症信号传导可改善重症患者的肺功能哮喘，雄激素信号传导的遗传变异是治疗的临床相关修饰剂这些患者的反应。我们提出以下具体目标：1）确定雄激素是否对严重哮喘患者刷取的 AEC 中的 S-亚硝基化和 pH 调节产生有利影响； 2) 至研究雄激素是否调节患有以下疾病的患者 AEC 中的促炎介质基因和蛋白表达严重哮喘； 3) 研究 DHEA 是否可以改善低血压哮喘患者的 FEV1 并降低 FeNO DHEA-S 水平和有利的 HSD3B1 基因型。拟议的研究意义重大，因为它们将提供更好地了解严重哮喘中雄激素信号传导的未知机制和目标。概念创新在几个层面上提供：首先，我们将确定雄激素的新机制严重哮喘 AEC 中的信号传导，并与亚硝基化/去亚硝基化、pH 值建立关键串扰调节和炎症。其次，我们将确定性别和雄激素作为 AEC-ASMC 串扰的调节剂。第三，我们将对 HSD3B1 在严重哮喘中的作用进行首次机制研究。结束后我们的研究，我们将确定雄激素信号传导的新颖且可治疗的靶向机制严重哮喘中的 AEC 和 ASMC，我们将确定一个新的男性和女性患者群体这将受益于基于激素的个性化和有针对性的治疗方法。