Gonadal hormones as mediators of sex and gender influences in asthma

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PROJECT SUMMARY MicroRNAs (miRNAs) are a class of small noncoding RNAs with ≤25 nucleotides that play a vital regulatory role in a wide range of cellular and biological processes, including immune regulation, apoptosis and inflammatory response. These posttranscriptional regulators fine-tune gene expression via direct translational inhibition and/or induction of target mRNA degradation. Abnormal miRNA expression has been associated with both the development and exacerbation of pulmonary disease, including asthma, COPD, and lung cancer among young and older populations. Yet, in spite of the known sex disparities in the incidence and severity of lung diseases, few studies have investigated the role of miRNAs in mediating such sex differences. The primary goal of this project is to investigate the role played by miRNAs in asthma development in males and females, by using a mouse model of house dust mite exposure available in the mentor’s laboratory. Prior studies from Dr. Silveyra’s laboratory (PI) in mice have reported sex differences and influences of circulating sex hormone levels in the lung inflammatory response to environmental exposures. Thus, in this study, we hypothesize that sex-specific miRNA expression mediates sex-specific immune responses activated during asthma, via modulation of pulmonary inflammatory gene expression. To test this hypothesis, we will assess differences in miRNA expression in sex chromosome complement and gonadal hormone asthma phenotypes using the four core genotypes mouse model (Aim 1). We will also evaluate the impact of sex hormones on miRNA expression in male and female lungs (Aim 2). Finally, we will identify estrogen receptor-induced miRNA signatures that contribute to asthma phenotypes (Aim 3). The training plan of the proposed IRS diversity supplement will enable the candidate to gain scientific knowledge and communication skills, become proficient in molecular physiology bench research techniques, and obtain preliminary data to acquire independent research funding. Training and mentoring will involve meetings with the mentor and her investigative team at Indiana University Bloomington, as well as with two additional faculty advisors, formal coursework, and seminars. Courses will focus on multi-omics approaches and personalized medicine to establish an understanding of the fundamental issues related to the design, conduct, analysis, and data interpretation. Coursework will be supplemented with training in laboratory techniques to establish an understanding of the pathobiology of lung disorders. This combination of mentoring and coursework will equip the candidate with the tools necessary to create a meaningful, effective, and sustainable research program.