HORMONAL INFLUENCES ON AIRWAY DISEASE

激素对气道疾病的影响

基本信息

批准号：
8429395
负责人：
Raksha Jain
金额：
$ 12.83万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8429395
关键词：
Accounting Address Adult Affect Air Asthma Breathing Bronchiectasis Cell Culture Techniques Cell Differentiation process Cell physiology Cell surface Cells Childhood Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Cilia Clinical Cystic Fibrosis Data Disadvantaged Disease Donor person Energy Metabolism Environment Epidemiologic Studies Epithelial Epithelial Cells Epithelium Estrogens Etiology Female Foundations Frequencies Gender Goals Gonadal Steroid Hormones Health High Prevalence Hormonal Hormone Receptor Hormones Human In Vitro Infection Label Lead Life Expectancy Ligands Liquid substance Lung Lung diseases Luteal Phase Mammalian Oviducts Measures Mediating Mentors Modeling Mucociliary Clearance Mucous body substance Mus Nitric Oxide Nitric Oxide Synthase Nose Nutritional Outcome Pathway interactions Patients Phase Phenotype Physicians Play Prevalence Production Progesterone Progesterone Receptors Puberty Recruitment Activity Recurrence Registries Regulation Relative (related person)Research Respiratory physiology Role Scientist Severities Sex Characteristics Specificity Sputum Structure of parenchyma of lung Supplementation Surface Symptoms Testing Woman Work airway epithelium base bench to bedside career cell type epidemiologic data hormone regulation improved in vivo indexing men mouse model novel novel therapeutic intervention pathogen patient registry programs public health relevance receptor receptor expression respiratory response trafficking

项目摘要

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.

描述（由申请人提供）：气道疾病是最常见的肺部疾病，但是，这些疾病的治疗仍然不足。流行病学数据表明，气道疾病患者在内的性别差异存在性别差异，包括支气管扩张，哮喘和慢性阻塞性肺部疾病，在某些情况下，女性表现出较差的严重性和更严重性和结果，并且患病率更高。很少有研究解决了这种差异的生物学基础，但是性激素是潜在的重要变量。对荷尔蒙对气道的影响的充分理解可能会导致新的疗法，以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仪在保护肺部免受病原体免受病原体的影响至关重要，并且是调节激素的靶标。实际上，我们的初步数据表明女性性激素会改变粘毛功能。因此，该提案的目的是确定性激素，特别是孕激素对粘膜纤毛清除的影响，作为对气道疾病性别差异的解释的基础。中心假设是，由于孕激素介导的上皮粘膜纤毛功能的改变，女性的气道疾病比男性更严重。这些研究的长期目标是了解导致气道疾病性别差异，改善当前治疗并发展新疗法的机制。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特定目标，将基于基准的方法应用于这一建议。在AIM 1中，我们将表征孕酮受体表达，细胞特异性和受体运输，在原发性气道细胞和人类肺组织中。在AIM 2中，我们将通过比较激素刺激条件下的原发性气道上皮细胞的纤毛频率以及测量激素操纵小鼠中的气道间隙，来确定孕酮对粘膜缩减清除的影响。我们还将评估影响气道上皮细胞功能的孕激素依赖性途径，以了解性激素对粘膜纤毛清除的影响。 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.对这些发现的进一步理解可能导致新的治疗方法，涉及支气管扩张和其他气道疾病中的激素操纵。这项工作结合了指导研究计划和有针对性的教育计划，将成为PI医师科学家职业的基础。