Project Summary Chronic rhinosinusitis (CRS) is a common inflammatory disease that affects a large portion of the U.S. population, resulting in poor quality of life for those affected and utilizing billions of dollars of health care resources. Unfortunately, CRS presents more like a heterogeneous syndrome than a distinct diagnostic entity, resulting in variability in both phenotype, symptoms, and inflammatory signatures. Consequently, CRS pathophysiology and associated mechanisms of disease remain poorly understood. Our group recently identified a unique inflammatory signature specific to elderly CRS patients, which is characterized by profound elevation of IL-1 and other pro-inflammatory cytokines. The central hypothesis of this proposal is that CRS in aged patients is associated with an age-dependent, IL-1-associated mechanism that derives from dysfunctional innate immunity and activation of the inflammasome. We will test this hypothesis by analyzing a large prospectively enrolled cohort of CRS patients. Specific Aim 1 will determine whether aging is associated with altered Toll-like receptor expression or function, with resultant ‘priming’ of the innate immune system. Aim 2 will determine whether aging in CRS patients results in increased inflammasome activation. We will subsequently analyze the ability of common microbial ligands and endogenous age-related inflammatory stimuli to activate inflammasome-associated cytokine production and release. Finally, in Specific Aim 3 we will determine whether there are functional associations between the sinonasal microbiome and/or individual pathogens with aging, innate immune function, and the IL-1-driven pro-inflammatory signature. This proposal seeks to characterize a previously unrecognized inflammatory subtype of CRS that affects aged individuals, a vulnerable population with limited medical and surgical options. Findings from this study will provide further insight into the mechanism of CRS and reveal previously unidentified associations between innate immune function, the sinus microbiota, and different types of chronic mucosal inflammation in the sinonasal cavity.