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In the U.S., rates are higher in females than in males for doctor-diagnosed asthma, current asthma, and asthma-related outpatient and emergency department visits, hospitalizations, and deaths. Although the reasons why females are more likely to have asthma are not entirely clear, a compelling body of epidemiologic evidence supports a role for sex hormones in modulating lung function, bronchial hyperresponsiveness and asthma in humans. Menstrual cycle variations in pulmonary function and bronchial hyperresponsiveness have been well documented (1, 2). Premenstrual asthma has been reported in up to 40% of asthmatic women and almost half of all female hospital admissions for asthma exacerbation occur during the premenstrual phase (3). Oral contraceptives significantly increase total lung capacity during the follicular phase of the menstrual cycle (4) and reduce premenstrual declines in pulmonary function among women with asthma (5). Postmenopausal women receiving hormone replacement therapy have higher forced expiratory volume in one second and significantly less airway obstruction than women not receiving hormone replacement (6). We have preliminary unpublished data to suggest that: 1) estrogen receptor-a is a critical regulator of respiration and airway hyperresponsiveness in naïve and allergic mice; and 2) male mice have exaggerated airway inflammatory and functional responses to bacterial products (e.g. lipopolysaccharide) compared to female mice, a phenomenon which appears to be mediated, at least in part, by detrimental effects of androgens.
The goal of this fellowship is to conduct translational research into the mechanisms that underlie gender differences in asthma and lung function. Our group has extensive expertise with laboratory mouse models of allergic airway disease and acute lung injury. We routinely measure airway inflammation and lung function following environmentally relevant exposures using state-of-the-art techniques and assess gene expression changes using microarray analysis combined with real-time quantitative polymerase chain reaction and the Bio-plex suspension array system. One example of a project for the fellow would be to examine the effect of gender on airway inflammatory and functional responses to allergic and non-allergic stimuli, and to determine the hormonal mechanisms involved using gonadectomized mice with/without exogenous hormone replacement and mice deficient in estrogen receptors a or ?, or the androgen receptor. In addition to laboratory expertise, we have extensive experience in conducting human observational and experimental studies. We are actively involved in the design, implementation and analysis of the respiratory component of the National Health and Nutrition Examination Survey (NHANES) as well as other large national studies. We will open a new clinical facility in Research Triangle Park, NC in early 2006 that will allow NIEHS researchers to conduct human studies involving assessment of lung function and airway inflammation following exposure to environmental agents. As part of this fellowship, the trainee will be encouraged to design and implement human studies that follow from his/her basic laboratory research. Our multidisciplinary research team consists of Immunologists (Michelle Carey, Dori Germolec), Respiratory Toxicologists (Dan Morgan, Jeff Card), Reproductive Endocrinologist (Ken Korach), Pulmonologist (Darryl Zeldin), and Epidemiologists (Samuel Arbes, Paivi Salo). We believe that we can provide an outstanding supportive environment for a fellow to pursue both bench and translational components of this project within a three year period.
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