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，在患有气道疾病（包括支气管扩张、哮喘和慢性阻塞性肺病）的患者中存在性别差异，在某些情况下，女性表现出更差的严重程度和结局沿着更高的患病率。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液纤毛器在保护肺免受病原体侵害方面起着关键作用，并且是激素调节的靶点。事实上，我们的初步数据表明，女性性激素改变粘液纤毛功能。因此，本提案的目标是确定性激素，特别是孕酮对粘膜纤毛清除的影响，作为解释气道疾病中性别差异的基础。中心假设是女性比男性有更严重的气道疾病，这是由于孕酮介导的气道上皮粘膜纤毛功能的改变。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，我们将通过在体外、体内和临床水平上追求三个具体目标，对该提案采用从实验室到临床的方法。在目标1中，我们将描述孕激素受体表达，细胞特异性，受体运输在原代人气道细胞和人肺组织。在目标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通过测量激素操作小鼠的气道清除率来确定孕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胆固醇依赖性途径，以了解性激素对粘液纤毛清除的影响机制。在目标3中，使用囊性纤维化（CF）支气管扩张作为气道疾病模型，我们将利用国家CF基金会登记研究回顾性比较青春期前和青春期后男性和女性的肺功能和肺加重，并在当地招募CF支气管扩张女性，以前瞻性评估排卵周期激素阶段的肺健康。对这些发现的进一步理解可能会导致新的治疗方法，包括支气管扩张和其他气道疾病的吸入激素操作。这项工作，与指导研究计划和有针对性的教育计划相结合，将作为PI的医生科学家职业生涯的基础。 公共卫生相关性：气道疾病是最常见的肺部疾病，目前治疗方法有限。多项流行病学研究表明，女性气道疾病的严重程度和预后比男性更差。本提案的目的是确定性激素对粘膜纤毛清除的影响和所涉及的途径。这些发现可能会导致新的治疗方法，包括吸入激素操纵支气管扩张症和其他气道疾病，如哮喘和慢性阻塞性肺疾病的患者。

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.