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?.
Asthma prevalence and severity varies with gender and age, but the mechanisms involved are unknown and understudied. Airway epithelial cells are at the front line of mucosal immunity and are a key component of asthma pathogenesis. We hope to identify novel mechanisms of asthma by establishing an understanding of how puberty-related changes in sex hormones promote gender-specific alterations in airway epithelial cell differentiation.
