Cellular and Molecular Mechanisms of the Pathogenesis of Aspirin Exacerbated Respiratory Disease

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ABSTRACT Dr. Whitney Stevens is a tenure-eligible Assistant Professor within the Division of Allergy and Immunology at the Northwestern University Feinberg School of Medicine. Her clinical and research interests focus on Aspirin Exacerbated Respiratory Disease (AERD), a disease consisting of the clinical triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma and sensitivity to inhibitors of the cyclooxygenase-1 enzyme. AERD is associated with significant morbidity, large socioeconomic burden, and negative impact on quality of life. Unfortunately, the underlying mechanisms of AERD pathogenesis are not well defined. As a result, current diagnostic and treatment options for affected patients remain limited, making AERD a large unmet clinical need. This career development award, under the mentorship of Dr. Robert Schleimer, focuses on investigating the cellular and molecular mechanisms of AERD pathogenesis to advance the understanding of this disease process. Dr. Stevens has preliminary evidence suggesting that basophils, as well as certain arachidonic acid metabolites, are elevated in nasal polyps of patients with AERD compared to patients with aspirin tolerant CRSwNP. The central hypothesis of the current proposal is that basophils and products of the 15-lipoxygenase pathway promote the exaggerated sinonasal inflammatory response and severe clinical characteristics observed in patients with AERD. This hypothesis will be addressed by 3 non-overlapping but complementary aims: 1) Correlation of the enhanced infiltration and activation of basophils with clinical disease severity in AERD; 2) Identification of the mechanisms responsible for the recruitment and activation of basophils in AERD nasal polyps; and 3) Examination and characterization of the effects of 15-lipoxygenase products in promoting the chronic inflammation observed in AERD nasal polyps. This study is innovative in that it will use novel recent data generated by Dr. Stevens to further investigate areas of AERD that are not currently well understood. This work will also lead to the expansion of what will become one of the largest clinically validated AERD cohorts available for study. Importantly, this award will provide Dr. Stevens with additional career development and training needed to build her own successful research team, establish independence from her mentor and significantly advance her career studying AERD pathogenesis.