Sunday, December 22, 2024
12/22/2024
Project Summary Asthma is a chronic inflammatory lung disease with a greater prevalence and severity in adult women than men. Mounting evidence suggests that sex differences in asthma are related to female steroid sex hormones, including estrogens. Estrogens have significant effects on lung function and responses to allergic challenge in male and female lung, acting via receptors including the estrogen receptors α and β (ERα and ERβ) and the G protein-coupled estrogen receptor (GPER). Prior studies from Dr. Silveyra’s laboratory (PI) have reported influences of circulating sex hormone levels in the lung inflammatory response to allergen challenge, using transgenic mouse models coupled with house dust mite (HDM) exposure. In this study, we will expand the studies conducted in the parent grant to characterize intracellular signaling cascades mediated by the GPER in the asthmatic bronchial epithelium. We hypothesize that the GPER mediates sex-specific responses activated during HDM allergen challenge. To test this hypothesis, we will assess the effect of HDM challenge in GPER signaling using human bronchial epithelial cells (HBEC) from asthmatic females and males (Aim 1). We will also evaluate sex differences in GPER signaling pathways and second messengers activated by HDM and estrogen in HBEC from asthmatic patients (Aim 2). The training plan of the proposed PDS diversity supplement is integrated with the experimental approach and will enable the candidate to gain scientific knowledge and communication skills, become proficient in molecular endocrinology and cell signaling bench skills, and obtain preliminary data to apply for independent research funding as a postdoctoral fellow. Training and mentoring will involve meetings with the primary mentor, Dr. Silveyra, her investigative team at Indiana University Bloomington, two additional faculty advisors (Dr. Hocevar and Dr. Owora), coursework, and seminars. Coursework will be supplemented with training in laboratory techniques to establish an understanding of the pathophysiology of lung diseases and research design to assess sex-specific mechanisms and incorporating sex as a biological variable. This combination of mentoring, bench training, and coursework will equip the candidate to build his research career and work towards providing a better understanding of the molecular mechanisms and pathways underlying lung diseases that differentially affect males and females.
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