Multi-omics Strategies to Improve Clinical Outcomes in Uveitis

PROJECT SUMMARY Uveitis is an inflammatory eye disease that confers severe ocular morbidity and can cause long term blindness if not diagnosed and treated promptly. Current challenges exist in the diagnosis of infectious cases due to inadequate clinical laboratory methods to establish the exact cause and the current sample volume requirement for multiple analysis. Technological advancements with high-throughput sequencing have improved diagnostic strategies in medicine and are enabling the detection of several types of infectious organisms. Additionally, biomarker discovery is lacking in uveitis. Herein we propose a collaboration with stakeholders both local and international to enhance the understanding of the pathogenesis of uveitis to improve upon uveitis classification, diagnosis, biomarker identification, and deepen our understanding of the host response with the following aims. In the first aim we will perform worldwide surveillance of pathogens causing uveitis, identify geographic trends, and assess the effect of pathogen class and antimicrobial resistance on visual outcomes. We expect we will identify known and unknown causes of infectious uveitis using metagenomic sequencing and that the organisms will vary by geographic locale and seasonality. Visual outcomes will vary by pathogen class. In the second aim we will characterize the host gene expression profiles in infectious uveitis and determine what profiles predict clinical outcomes. We will identify host transcriptome signatures that will vary by pathogen class and determine the profiles implicated in clinical outcomes. In the last aim we will interrogate the tears for noninvasive biomarker discovery using the proteome and metabolomic signatures. These aims combine the characterization of pathogens, host transcriptomes, and the tear proteome and metabolite signatures to provide a comprehensive molecular approach to improve the diagnosis of uveitis. We will leverage international collaborators to use newer laboratory techniques with unbiased RNA deep sequencing and mass spectrometry. This will contribute to further our understanding of the eye as a surveillance site for infectious diseases and is paramount for establishing disease causality and will impart knowledge and data into public health priorities, programs, and policy.