Gender-specific effects of puberty on airway epithelial differentiation in asthma

青春期对哮喘气道上皮分化的性别特异性影响

• 批准号: 10455533
• 负责人: Sergio E Chiarella
• 金额: $ 18.58万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455533
• 关键词: Affect; Age; Asthma; Bioinformatics; Bronchoalveolar Lavage Fluid; Cell Differentiation process; Cells; Communication; Data; Data Analyses; Development; Down-Regulation; Epithelial; Epithelial Cells; Estrogens; Exhibits; Experimental Designs; Female; Fibroblast Growth Factor Receptor 2; Fostering; Gender; Gene Expression Profile; Genes; Goals; Gonadal Steroid Hormones; Hospitalization; Human; Immune; Interleukin-4; Interleukin-5; Knowledge; Laboratory Procedures; Lung; Mediating; Mentors; Messenger RNA; Modeling; Morbidity - disease rate; Mucosal Immunity; Mus; Ovalbumin; Pathogenesis; Pathway Analysis; Pattern; Peer Review; Permeability; Phenotype; Physicians; Play; Prevalence; Process; Puberty; Public Health; Publishing; Regulation; Research; Role; Scientist; Severities; Sex Differences; Signal Transduction; Testing; Time; Training; Training Programs; United States; Universities; Up-Regulation; Woman; aged; airway epithelium; asthma exacerbation; asthma model; asthmatic; asthmatic airway; asthmatic patient; boys; clinically relevant; design; eosinophil; epidemiologic data; epithelial to mesenchymal transition; girls; hormone regulation; in vivo; laboratory experience; male; men; mouse model; new therapeutic target; novel; prepuberty; programs; sex; sexual dimorphism; skills; young adult

PROJECT SUMMARY/ABSTRACT The main objectives of this K08 proposal are: 1) to foster the development of essential scientific and professional skills that will allow the candidate, Dr. Sergio Chiarella, to achieve a long-term goal of becoming an independent physician-scientist concentrating on the role of sex hormones in asthma pathogenesis, and 2) to investigate the gender-specific effects of puberty-related systemic changes in sex hormones on airway epithelial differentiation in asthma. Through laboratory experience, coursework in Northwestern University's Program in Public Health, and the peer review process, Dr. Chiarella will gain expertise in experimental design, laboratory procedures, data analysis, and scientific communication. Dr. Chiarella and his mentors at Northwestern University, Drs. Sergejs Berdnikovs and Robert Schleimer, have designed a specific training plan that will allow Dr. Chiarella to gain new knowledge and research skills in asthma. Asthma is a lung condition that causes tremendous morbidity in the United States. There is ample epidemiological data showing that asthma prevalence and severity is gender-specific and changes with puberty. Pre-pubertal boys have an increased prevalence of asthma and rate of asthma exacerbations requiring hospitalization compared to pre-pubertal girls. Interestingly, this pattern reverses with the onset of puberty and is known as the “asthma puberty switch”. The mechanisms involved in the “asthma puberty switch” are poorly understood and understudied. Our preliminary data identify airway epithelial differentiation as a critical target of sex hormones. Furthermore, our results show that the loss of airway epithelial differentiation and function is gender-specific. Thus, we hypothesize that puberty-related systemic changes in sex hormones promote a gender-specific effect on airway epithelial differentiation in asthma. To test this hypothesis, we propose the following Specific Aims: 1) determine whether human normal and asthmatic airway epithelium differentiation is gender-specific, and 2) determine the sex-specific effects of puberty on airway epithelial differentiation and FGFR2 signaling in a murine “puberty switch” model of asthma. To specifically test our hypothesis, we have developed a murine model of asthma which replicates the “asthma puberty switch” seen in humans. We have also developed organotypic cultures of primary human airway epithelial cells to evaluate the effects of estrogen on basal (less differentiated) and ciliated (more differentiated) epithelial cells. Finally, we propose to identify the in vivo effects of sex hormones and FGFR2 on the airway epithelial barrier using gonadectomized mice and Fgfr2fl/flFoxj1Cre mice, respectively. Successful execution of these aims will provide a rigorous training program for Dr. Chiarella and uncover mechanisms involved in the “asthma puberty switch”.

项目概要/摘要 K08 提案的主要目标是： 1) 促进基本科学和专业知识的发展 使候选人 Sergio Chiarella 博士能够实现成为独立人士的长期目标的技能 专注于性激素在哮喘发病机制中的作用的医师科学家，以及 2) 研究 青春期相关性激素全身变化对气道上皮分化的性别特异性影响 在哮喘中。通过实验室经验和西北大学公共卫生项目的课程， 和同行评审过程中，Chiarella 博士将获得实验设计、实验室程序、 数据分析和科学交流。 Chiarella 博士和他在西北大学的导师 Drs. Sergejs Berdnikovs 和 Robert Schleimer 设计了一项具体的培训计划，使 Chiarella 博士能够 获得哮喘方面的新知识和研究技能。哮喘是一种导致极高发病率的肺部疾病 在美国。有大量流行病学数据表明哮喘患病率和严重程度 具有性别特异性并随青春期而变化。青春期前男孩哮喘患病率和发病率增加 与青春期前的女孩相比，需要住院治疗的哮喘发作的比例。有趣的是，这个模式 随着青春期的开始而逆转，被称为“青春期哮喘开关”。涉及的机制 人们对“哮喘青春期转换”知之甚少，研究也不足。我们的初步数据确定了气道 上皮分化是性激素的关键目标。此外，我们的结果表明，气道损失 上皮细胞的分化和功能具有性别特异性。因此，我们假设与青春期相关的系统性 性激素的变化促进对哮喘气道上皮分化的性别特异性影响。测试 针对这一假设，我们提出以下具体目标：1）确定人类是否正常和哮喘 气道上皮分化具有性别特异性，并且 2) 确定青春期对气道的性别特异性影响 小鼠哮喘“青春期转换”模型中的上皮分化和 FGFR2 信号传导。来具体测试一下 我们的假设是，我们开发了一种哮喘小鼠模型，它复制了所见的“哮喘青春期转换” 在人类中。我们还开发了原代人气道上皮细胞的器官型培养物来评估 雌激素对基底（分化程度较低）和纤毛（分化程度较高）上皮细胞的影响。最后，我们 提议使用以下方法确定性激素和 FGFR2 对气道上皮屏障的体内影响 分别是去性腺切除小鼠和 Fgfr2fl/flFoxj1Cre 小鼠。这些目标的成功执行将提供 为 Chiarella 博士提供严格的培训计划，并揭示“哮喘青春期转换”的机制。