Androgen signaling in asthma

哮喘中的雄激素信号传导

• 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
• 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

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.

项目摘要/摘要 哮喘是一种性二态性疾病，女性表现出较高的哮喘患病率和更严重的 表现比男人。项目3基于这样的理由，即雄激素（例如睾丸激素）和 脱氢表雄酮（DHEA）与哮喘的更好结果有关。但是，机制 雄激素介导的气道生物学调节仅是不完全理解的。此外，目前尚不清楚是否 雄激素治疗对严重哮喘是有益的，如果存在特定的患者人群可以针对的 通过精确的医学方法。项目3旨在填补这一知识差距并识别小说，以治疗 雄激素介导的肺功能改善的目标机制。最终，这将导致小说， 针对任何性别严重哮喘患者的靶向和皮质类固醇疗法。我们已经生成了 有趣的新数据表明，雄激素与人类哮喘气流之间的因果关系 梗阻。特别是，我们发现在患有轻度哮喘和低硫硫酸血浆水平的女性中，DHEA 治疗与FEV1的显着改善有关。其次，我们在一系列严重的队列中发现 哮喘患者是基因HSD3B1的位置1245的变体（编码增加组织的酶 如果DHEA-S血浆水平较低，则雄激素水平与较低的FEV1有关。第三，我们发现增加 气道上皮细胞中的雄激素受体mRNA丰度（AEC）与改善的肺功能有关 和更少的哮喘症状。这些数据导致我们假设雄激素对S-产生有益的影响 硝基化，pH调节和炎症信号传导可改善严重患者的肺功能 哮喘和雄激素信号传导中的遗传变异是治疗的临床改性剂 这些患者的反应。我们提出以下特定目的：1）确定雄激素是否是否 严重哮喘患者的AEC中，有利影响S-亚硝基化和pH调节； 2）到 研究雄激素是否调节来自患者的AEC的促炎介质基因和蛋白质的表达 严重的哮喘； 3）调查DHEA是否改善了FEV1并减少了低的Feno DHEA-S水平和有利的HSD3B1基因型。拟议的研究很重要，因为它们将提供 更好地理解严重哮喘中雄激素信号的未知机制和靶标。 概念创新在几个层面上提供：首先，我们将确定雄激素的新型机制 在严重哮喘中的AEC中发出信号，并建立硝基化/脱硝基化的临界串扰，pH 调节和炎症。其次，我们将确定性别和雄激素是AEC-ASMC串扰的修饰符。 第三，我们将对HSD3B1在严重哮喘中的作用进行首次机械研究。结束 我们的研究，我们将确定雄激素信号传导的新颖和治疗靶向的机制 严重哮喘中的AEC和​​ASMC，我们将确定新的男性和女性患者人群 这将受益于个性化和有针对性的基于激素的治疗​​方法。