The Modulation of Eotaxin Expression by Statins: Implications for Asthma Therapy

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DESCRIPTION (provided by applicant): The primary goal of this K08 proposal is to help me become an independent investigator with NIH R01 level funding. I have chosen as primary mentor Professor Reen Wu, who is a national leader in his field with a successful and long track record of prior mentees. As a fellow I initially worked in the laboratory of Dr. Nicholas Kenyon and learned to use the ovalbumin mouse model. This led to preliminary experiments in mouse and human airway epithelial cells to determine whether statins ameliorate allergic inflammation and epithelial injury, and if so, by what mechanisms. In 2009, I was awarded an American Thoracic Society (ATS) Career Development Award to study simvastatin's effects on airway remodeling via mevalonate (MA) pathway inhibition. Since then I also formed several collaborations both locally and with colleagues at other institutions that have led to a funded grant (TRDRP) and several publications. Throughout my fellowship and post-doctoral years I attended post-graduate courses and seminars at regional meetings and at the ATS annual international conferences. As a current K12 (KL2) scholar, I helped co-develop novel methodologies via our Metabolomics Core for measuring and quantifying the statins and MA metabolites in lung tissue. In 2012, I was appointed as an Assistant Professor in Residence, which is a research-focused academic series. This appointment is rewarding and demonstrates our Institution's commitment to my career development. This K08 proposal builds on my prior work and will lay the foundations to secure future R01 funding. Environment: The overall research environment at U.C. Davis is outstanding and well-suited for my research and career development goals. The Center for Comparative Respiratory Biology & Medicine provides for first class continuous and rich intellectual exchange among research faculty, graduate students, and clinical fellows. The College of Biological Sciences holds weekly Seminars in Molecular Biology that feature world- class speakers from all fields of molecular biology. U.C. Davis has a long history of training pre- and post- doctoral research trainees in pulmonary research through the Schools of Medicine and Veterinary Medicine, and California National Primate Research Center. Lung research in these schools is particularly strong with many NIH-funded investigators and recognized experts working in close proximity. Our Clinical and Translational Science Center (CTSC) and CTSC Clinical Research Center provide for continuous research infrastructure support, a resource I am very familiar with here at U.C. Davis. Career Goals: My overarching career goal is to become an independent and productive physician-scientist at an academic medical center, with clinical and basic science expertise in airway diseases such as asthma. My vision is to lead a laboratory that will investigate airway epithelial biology and pathogenic mechanisms relevant to airway diseases and perhaps other lung diseases, and develop innovative and novel therapies. Eventually, I will also mentor and train residents, fellows, graduate students, and junior faculty in their research and academic careers. Career Development Plan: This plan has 4 domains of training (during a 3-year award period): Research Skills, Coursework and Training, Manuscripts, and Grants. I have outlined an individualized educational plan with different percent efforts to highlight the development of my research program. I will devote at least 75% of my time to research, which fits well with the 25% clinical time including severe asthma clinic (1/2 day/week), in- patient rotations (6 weeks/year), and administrative duties/weekly seminars/lectures. This plan includes a mentoring team and Advisory Committee with regular planned meetings to gauge my progress. Research Project: Asthma symptoms remain poorly controlled in some asthmatics despite current treatments. The eotaxins(-1,2,3) are potent TH2 eosinophil-specific chemokines, important in severe asthma. Eotaxin-3 in particular is strongly associated with marked airway and systemic allergic inflammation, and increased asthma susceptibility. Observational studies and small clinical trials suggest that the lipid-lowering statin drugs may improve lung health. In our mouse model, we found that simvastatin (Sim) attenuates eosinophilic airway inflammation, IL13/IL4 production, and airway hyperreactivity. Using primary normal human bronchial epithelial cells, Sim suppressed basal and IL13-induced eotaxin-2 and -3 expression and STAT6 phosphorylation, without altering eotaxin-3 mRNA stability. Since eotaxin expression is under direct IL13-induced JAK/STAT6 transcriptional regulation, I hypothesize that simvastatin (1) inhibits airway epithelial eotaxin-2 and -3 gene expression at the transcriptional level through modulation of IL13-induced JAK/STAT6 signaling, and (2) reduces exacerbations in patients with severe allergic asthma. Specific Aims: Aim 1) To test whether Sim inhibits both basal and IL13-induced eotaxin gene expression at the transcriptional level. Aim 2) To test whether Sim inhibits the IL13-induced JAK/STAT6 signaling pathway. Aim 3) To determine whether Sim (A) decreases mediators of TH2 allergic inflammation in bronchial epithelial cells, and (B) reduces acute exacerbations and improves lung function. I will perform a 30-week prospective, double-blinded, cross-over early Phase II clinical trial and randomize severe asthma patients to both placebo and Sim for 12 week intervals, in addition to standard-of-care inhaled corticosteroid and long-acting β-agonist.