HORMONAL INFLUENCES ON AIRWAY DISEASE

描述(申请人提供)：呼吸道疾病是最常见的肺部疾病，然而，这些疾病的治疗仍然不够。流行病学数据表明，包括支气管扩张、哮喘和慢性阻塞性肺疾病在内的呼吸道疾病患者存在性别差异，在某些情况下，女性表现出更差的严重性和预后，同时患病率增加。很少有研究探讨这种差异的生物学基础，但性激素是一个潜在的重要变量。充分了解荷尔蒙对呼吸道的影响可能会导致新的疗法来帮助治疗这些令人衰弱的疾病。在呼吸道疾病中，由纤毛、粘液和呼吸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袭方面起着关键作用，也是激素调节的靶标。事实上，我们的初步数据表明，女性性激素改变了粘液纤毛功能。因此，这项建议的目标是确定性激素，特别是黄体酮对粘液纤毛清除的影响，作为解释呼吸道疾病性别差异的基础。中心假设是，由于黄体酮介导的呼吸道上皮粘液纤毛功能的改变，女性比男性有更严重的呼吸道疾病。这些研究的长期目标是了解导致呼吸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。为了解决这些长期目标，我们将通过在体外、体内和临床水平上追求三个具体目标，对这项建议应用床到床的方法。在目标1中，我们将表征原代人呼吸道细胞和人肺组织中孕酮受体的表达、细胞特异性和受体转运。在目标2中，我们将通过比较原代人呼吸道上皮细胞在激素刺激条件下的纤毛搏动频率和通过测量激素操纵的小鼠的气道清除来确定黄体酮对粘液纤毛清除的影响。我们还将评估影响呼吸道上皮细胞功能的孕激素依赖途径，以了解性激素影响粘膜纤毛清除的机制。在目标3中，使用囊性纤维化(CF)支气管扩张症作为一种模型呼吸道疾病，我们将利用国家CF基金会登记，回顾比较男性和女性在青春期前后的肺功能和肺恶化情况，并在当地招募CF支气管扩张症妇女，以前瞻性地评估排卵周期荷尔蒙阶段的肺健康状况。对这些发现的进一步了解可能会导致新的治疗方法，包括对支气管扩张和其他呼吸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，将成为PI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.