PROJECT SUMMARY We will create a new dual approach for discovering and developing targeted autoimmune therapeutics. Recent work has highlighted the role of B cells in Neuromyelitis Optica (NMO) disease progression, and autoimmune B cells are a major target for NMO therapeutics. In this project, we will apply a single B cell molecular analysis pipeline to understand the features of autoimmune B cells, and in parallel we will develop a set of new molecular probes designed to silence autoimmune B cells associated with NMO. We will focus our analysis on aquaporin 4, the predominant autoantigen in NMO. We will also apply our molecular-scale technologies to evaluate the ability of these new probes to capture the full set of autoimmune antibodies and autoimmune B cells in NMO patients. This project represents the first step of a broader research program in the guided development and analysis of targeted molecular therapeutics to treat human autoimmune diseases, beginning with NMO.