HORMONAL INFLUENCES ON AIRWAY DISEASE

描述（由申请人提供）：呼吸道疾病是最常见的肺部疾病，然而，对这些疾病的治疗仍然不足。流行病学数据表明，在包括支气管扩张、哮喘和慢性阻塞性肺病在内的气道疾病患者中存在性别差异，在某些情况下，女性表现出更严重的程度和更严重的后果，同时患病率也有所增加。很少有研究涉及这种差异的生物学基础，但性激素是一个潜在的重要变量。充分了解激素对气道的影响可能会导致新的疗法来帮助治疗这些使人衰弱的疾病。在气道疾病中，由纤毛、粘液和气道上皮细胞表面液体组成的粘膜纤毛器在保护肺部免受病原体侵害方面起着关键作用，是激素调节的靶点。事实上，我们的初步数据表明，女性性激素会改变纤毛粘膜功能。因此，本提案的目标是确定性激素，特别是黄体酮，对粘膜纤毛清除的影响，作为解释气道疾病性别差异的基础。中心假设是，由于黄体酮介导的气道上皮粘膜纤毛功能改变，女性比男性有更严重的气道疾病。这些研究的长期目标是了解导致气道疾病性别差异的机制，改进当前的治疗方法，并开发新的治疗方法。为了实现这些长期目标，我们将通过追求体外、体内和临床水平的三个具体目标，对该提案应用从实验台到临床的方法。在Aim 1中，我们将描述孕激素受体在人气道细胞和肺组织中的表达、细胞特异性和受体运输。在Aim 2中，我们将通过比较激素刺激条件下原代人气道上皮细胞的纤毛搏动频率和激素操纵小鼠的气道清除率来确定黄体酮对粘膜纤毛清除率的影响。我们还将评估影响气道上皮细胞功能的黄体酮依赖通路，以了解性激素影响纤毛粘膜清除的机制。在Aim 3中，我们将使用囊性纤维化（CF）支气管扩张作为模型气道疾病，我们将利用国家CF基金会登记来回顾性比较男性和女性在青春期前和青春期后的肺功能和肺恶化，并招募当地CF支气管扩张女性在排卵周期的激素阶段前瞻性评估肺健康。进一步了解这些发现可能会导致新的治疗方法，包括吸入激素操作支气管扩张和其他气道疾病。这项工作与指导研究计划和有针对性的教育计划相结合，将成为PI的医生-科学家职业生涯的基础。

DESCRIPTION (provided by applicant): Airway diseases are the most common of the lung disorders, however, treatment for these illnesses remains inadequate. Epidemiologic data indicates that a gender disparity exists in patients with airway diseases including bronchiectasis, asthma, and chronic obstructive lung disease, with women demonstrating worse severity and outcomes along with an increased prevalence in some circumstances. Few studies have addressed the biologic basis of this disparity, but sex hormones are a potentially important variable. A full understanding of the hormonal influences on the airways may lead to novel therapies to help treat these debilitating illnesses. In airway disease, the mucociliary apparatus, made up of cilia, mucous, and airway epithelial cell surface liquid, plays a critical role in protecting the lung from pathogens and is a target for hormone regulation. Indeed, our preliminary data indicates that female sex hormones alter mucociliary function. Accordingly, the goal of this proposal is to determine the impact of sex hormones, specifically progesterone, on mucociliary clearance, as a basis of explanation for the gender disparity in airways diseases. The central hypothesis is that women have more severe airway diseases than men due to progesterone-mediated alterations in airway epithelial mucociliary function. The long term goals of these studies are to understand the mechanisms leading to gender differences in airway diseases, improve current treatment, and develop novel therapies. To address these long term goals, we will apply a bench-to-bedside approach to this proposal by pursuing three specific aims at the in vitro, in vivo, and clinical levels. In Aim 1, we will characterize progesterone receptor expression, cell specificity, and receptor trafficking in primary human airway cells and in human lung tissues. In Aim 2, we will determine the impact of progesterone on mucociliary clearance by comparing cilia beat frequency of primary human airway epithelial cells in hormone stimulated conditions and by measuring airway clearance in hormone manipulated mice. We will also evaluate progesterone-dependent pathways that influence airway epithelial cell function to understand the mechanisms involved in sex hormone influences on mucociliary clearance. In Aim 3, using Cystic Fibrosis (CF) bronchiectasis as a model airway disease, we will utilize the national CF Foundation registry to retrospectively compare lung function and pulmonary exacerbations in men and women pre- and post-puberty and recruit CF bronchiectasis women locally to prospectively assess lung health during hormonal phases of the ovulatory cycle. Further understanding of these findings could lead to new therapeutic approaches involving inhaled hormone manipulation in bronchiectasis and other airway diseases. This work, in combination with a program of mentored research and a targeted educational program, will serve as the foundation for the PI's physician-scientist career. PUBLIC HEALTH RELEVANCE: Airway diseases are the most common of the lung diseases, and currently have limited therapies. Multiple epidemiologic studies indicate that women with airway diseases have increased severity and worse outcomes than men. The objective of this proposal is to identify the influences of sex hormones on mucociliary clearance and the pathways involved. These findings could lead to novel therapeutic approaches involving inhaled hormone manipulation in patients with bronchiectasis and other airway diseases such as asthma and chronic obstructive pulmonary disease.