Core B: Integrative Genomics Core ABSTRACT This U19 re-competing proposal entitled “Pathophysiologic and Therapeutic Mechanisms of Aspirin Exacerbated Respiratory Disease” seeks to understand the mechanisms of chronic rhinosinusitis with nasal polyposis (CRSwNP) and aspirin exacerbated respiratory disease (AERD) at a multi-omic molecular and cellular level. The Integrative Genomics Core (IGC) will utilize cutting-edge technologies and computational methods, many of which were developed by our group, to support the objectives of the three Projects, each of which is focused on a different aspect of Type II immunopathology (T2I). The IGC will be based at the Raychaudhuri lab at the Brigham and Women’s Hospital (BWH), where the BWH Single Cell Genomics Core is also based. The IGC is composed of researchers with 10+ years of experience leading large-scale functional genomics projects, processing large datasets, and performing statistical analyses to integrate different layers of multi-dimensional information for the understanding of immune-mediated diseases. The IGC has a robust informatics infrastructure where terabytes of data can be stored and high-performance computing jobs can be run. Specifically, the IGC will (i) generate the single-cell and bulk datasets profiling RNA, open chromatin and protein levels for all three Projects, (ii) process and perform the quality check of each dataset, (iii) apply normalization and batch correction procedures, (iv) perform reproducible bioinformatic and statistical analyses, and (v) archive all experimental data and results on a firewall and password protected internal network. The IGC will perform analyses according to each Project’s needs to gain insights into mast cell heterogeneity and differentiation (Project 1), basal cell differentiation and senescence programs (Project 2), and the molecular underpinnings of drug response in a clinical trial (Project 3). Additionally, the IGC will facilitate synergy and data integration across all three Projects, contributing to new mechanistic insights into the control and therapy of T2I in CRSwNP and AERD.