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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

基本信息

批准号：
10663261
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
项目类别：
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/10663261
关键词：
Affect Age Asthma Bioinformatics Bronchoalveolar Lavage Fluid Cell Differentiation process Cells Communication Data Data Analyses Development Down-Regulation Epithelial Cells Epithelium 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 Micro Array Data 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 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

项目摘要

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”.

项目总结/摘要 K 08提案的主要目标是：1）促进基本科学和专业知识的发展，技能，这将使候选人，塞尔吉奥Chiarella博士，实现成为独立的长期目标医生科学家专注于性激素在哮喘发病机制中的作用，2）调查青春期相关性激素系统变化对气道上皮分化的性别特异性影响哮喘病通过实验室经验，西北大学公共卫生课程，和同行评议过程中，Chiarella博士将获得专业知识，在实验设计，实验室程序，数据分析和科学交流。奇亚雷拉博士和他在西北大学的导师们。 Sergejs Berdnikovs和Robert Schleimer设计了一个具体的培训计划，可以让Chiarella博士获得哮喘的新知识和研究技能。哮喘是一种肺部疾病，导致巨大的发病率在美国有大量的流行病学数据表明，哮喘的患病率和严重程度是性别特异性和青春期的变化。青春期前男孩哮喘患病率和与青春期前女孩相比，哮喘急性发作需要住院治疗。有趣的是，随着青春期的开始而逆转，被称为“哮喘青春期转换”。涉及的机制对“哮喘青春期转换”了解甚少，研究不足。我们的初步数据确定了气道上皮分化作为性激素的关键目标。此外，我们的研究结果表明，上皮分化和功能是性别特异性的。因此，我们假设青春期相关的系统性性激素的变化促进了哮喘气道上皮分化的性别特异性效应。测试基于这一假设，我们提出以下具体目的：1）确定人类正常和哮喘患者是否气道上皮分化具有性别特异性，2）决定青春期对气道的性别特异性影响哮喘小鼠“青春期转换”模型中的上皮分化和FGFR 2信号传导。专门测试根据我们的假设，我们已经建立了一个小鼠哮喘模型，它复制了我们所看到的“哮喘青春期转换”，在人类身上。我们还开发了原代人气道上皮细胞的器官型培养，以评估雌激素对基底上皮细胞（分化程度较低）和纤毛上皮细胞（分化程度较高）的影响。最后我们建议使用以下方法鉴定性激素和FGFR 2对气道上皮屏障的体内作用：性腺切除小鼠和Fgfr 2fl/flFoxj 1Cre小鼠。这些目标的成功实现将提供一个严格的培训计划，并揭示机制参与了“哮喘青春期开关”。