Particulate matter size, epithelial barrier dysfunction, and chronic rhinosinusitis - ABSTRACT Goal: The proposal outlined in this career development award (CDA) will provide Dr. Amarbir S. Gill with the protected time and training needed to develop into a successful, independent clinician-scientist. Dr. Gill's long- term career goal is to develop a translational research program that employs advanced molecular laboratory techniques to elucidate effects of environmental exposures on sinonasal epithelial barrier dysfunction in chronic rhinosinusitis (CRS) and identify key management strategies. Training: To achieve his goal, Dr. Gill has assembled a mentorship team that takes advantage of deep expertise in epithelial pathobiology, environmental exposures, label-free imaging, and bioinformatics at the University of Michigan, and has a strong track-record of mentoring K awardees to independence. Research: CRS is a debilitating inflammatory disease of the upper airway that affects up to 12% of the U.S. population. People with CRS battle daily nasal congestion, smell loss, nasal drainage, facial pain, as well as chronic fatigue, and sleep and cognitive dysfunction. The quality-of-life (QOL) impairment associated with CRS is on par with that of coronary artery disease, Parkinson's disease, and end stage renal disease. Despite its wide prevalence and significant morbidity, CRS remains an under- researched disease with limited effective treatment options. Available therapies fail to help more than 250,000 patients annually who then undergo sinus surgery, underscoring a critical need for improved knowledge of underlying molecular mechanisms driving disease pathophysiology. To this end, recent investigations have demonstrated that particulate matter (PM) exposure can increase the risk of developing CRS, while also impacting disease severity and surgical outcomes. We have shown these observations to be consistent for small, but not large PM particles. The present proposal seeks to understand the differential epithelial penetration and pathogenic potential of small vs. large PM particles, while identifying the role of sinonasal tight junctions (TJs) in propagating PM-mediated dysfunction of the sinonasal epithelial barrier in CRS. Our central hypothesis is that compared to large PM, smaller PM particles exhibit better sinonasal tissue penetration, allowing them to enter epithelial cells and initiate epithelial barrier dysfunction by downregulating key TJs, such as claudin proteins. To study this hypothesis, we will innovatively adapt fluorescence lifetime imaging microscopy (FLIM) – a label-free imaging tool that leverages differences in the autofluorescence spectra of PM and epithelial cells to track the movement of small and large PM particles – to in vitro air-liquid interface cell cultures and sinus biospecimens from individuals with CRS with nasal polyps, the most severe form of CRS. In doing so, we will define mechanisms facilitating size-dependent PM modulation of disease, uncover potential therapeutic targets, and inform novel management strategies.
