Androgen signaling in asthma

项目总结/摘要 哮喘是一种两性疾病，女性哮喘患病率更高， 表现比男人。项目3建立在雄激素如睾酮和 脱氢表雄酮（DHEA）与哮喘的更好结局有关。然而， 雄激素介导的气道生物学调节只是不完全了解。此外，目前尚不清楚， 雄激素治疗对严重哮喘有益，如果存在特定的患者群体， 通过精准医学的方法。项目3旨在填补这一知识空白， 雄激素介导的肺功能改善的靶向机制。最终，这将导致小说， 针对任何性别的严重哮喘患者的靶向治疗和皮质类固醇保留治疗。我们已经生成 有趣的新数据表明雄激素和缓解人类哮喘气流之间的因果关系 梗阻特别是，我们发现在轻度哮喘和低DHEA-硫酸盐血浆水平的女性中， 治疗与FEV1的显著改善相关。其次，我们发现在一组严重的 哮喘患者的基因HSD3B1（编码一种酶， 如果DHEA-S血浆水平低，雄激素水平）与较低的FEV1相关。第三，我们发现， 气道上皮细胞雄激素受体mRNA丰度与肺功能改善相关 更少的哮喘症状。这些数据使我们假设雄激素对S- 亚硝酰化、pH调节和炎症信号传导，导致严重肺结核患者肺功能改善 哮喘，雄激素信号传导的遗传变异是治疗哮喘的临床相关调节剂， 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 有利地影响严重哮喘患者刷拭的AEC中的S-亚硝基化和pH调节; 2） 雄激素是否调节前列腺癌患者AEC中促炎介质基因和蛋白表达研究 研究DHEA是否能改善哮喘患者的FEV_1和降低FeNO， DHEA-S水平和有利的HSD3B1基因型。拟议的研究是重要的，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靶点。 概念创新提供了几个层次：首先，我们将确定新的机制，雄激素 在严重哮喘的AEC中的信号传导，并建立与亚硝基化/去亚硝基化、pH 调节和炎症。其次，我们将确定性别和雄激素作为AEC-ASMC串扰的修饰剂。 第三，我们将进行HSD3B1在严重哮喘中作用的第一个机制研究。结束后 我们的研究，我们将确定新的和治疗的雄激素信号转导机制， 严重哮喘患者中的AEC和ASMCs，我们将确定一个新的男性和女性患者群体 这将受益于个性化和有针对性的治疗方法。

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.