Androgen signaling in asthma

项目摘要/摘要 哮喘是一种性两面性疾病，女性哮喘患病率更高，病情更严重。 比男人更有表现力。项目3的理论基础是雄激素，如睾酮和 脱氢表雄酮(DHEA)与哮喘的治疗效果有关。然而，这一机制 雄激素对呼吸道生物学的调节作用尚不完全清楚。此外，目前还不清楚是否 雄激素治疗对严重哮喘是有益的，如果存在特定的患者群体，可以进行靶向治疗 通过一种精确的医学方法。项目3旨在填补这一知识空白，并从治疗的角度确定新的 雄激素介导的改善肺功能的靶向机制。最终，这将导致小说， 针对严重哮喘患者的靶向和非皮质类固醇治疗，无论男女。我们已经产生了 耐人寻味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 障碍物。特别是，我们发现在患有轻度哮喘和低脱氢表雄酮-硫酸盐血浆水平的女性中，脱氢表雄酮 治疗与FEV1的显著改善有关。第二，我们发现在一群严重的 哮喘患者HSD3B1基因1245位变异(编码一种增加组织的酶) 如果脱氢表雄酮-S血浆水平较低，则与较低的FEV1相关。第三，我们发现增加了 呼吸道上皮细胞雄激素受体mRNA丰度与肺功能改善相关 哮喘症状也更少。这些数据让我们假设，雄激素对S有好处-- 亚硝酸化、pH调节和炎症信号导致重症患者肺功能的改善 哮喘，雄激素信号的遗传变异是治疗的临床相关修饰物 这些患者的反应。我们提出了以下具体目标：1)确定雄激素 对重症哮喘患者刷毛AEC的S亚硝化和pH调节有积极影响；2) 雄激素对慢性阻塞性肺疾病患者血管内皮细胞促炎介质基因和蛋白表达的影响 3)探讨脱氢表雄酮能否改善哮喘患者的FEV1，降低FENO。 脱氢表雄酮-S水平和有利的HSD3B1基因型。拟议的研究具有重要意义，因为它们将提供 更好地了解雄激素信号在严重哮喘中的未知机制和靶点。 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 重症哮喘患者AECs中的信号转导及与亚硝化/脱亚硝化、pH的临界串扰 调节和炎症。其次，我们将确定性和雄激素是AEC-ASMC相声的修饰物。 第三，我们将首次对HSD3B1在严重哮喘中的作用进行机制研究。在……结束时 我们的研究，我们将确定新的和治疗靶向的机制雄激素信号在 AECS和ASMC在重症哮喘中的作用，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基于激素的治疗方法。

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.