ABSTRACT Inflammatory signaling by macrophages in response to pathogens or tissue injury is the key determinant of the pathology and pathogenesis of infectious and non-infectious disease. The transcription factor NFκB controls the inflammatory gene expression programs, but it remains unclear how its regulation determines healthy or disease-associated gene expression responses. During the previous funding period, we have used a combined experimental / computational modeling approach to gain a predictive understanding of how NFκB is activated in response to TLR signaling and that multiple mechanisms converge to regulate NFκB. After developing a live cell microscopy tracking workflow we discovered that contrary to previous notions NFκB dynamics are highly oscillatory. By generating a knockin RelA-Venus mouse, we are able – for the first time – measure NFκB dynamics in primary cells revealing oscillations as an intrinsic hallmark of NFκB in healthy macrophages. Based on preliminary studies, we propose to test the hypothesis that NFκB oscillations are critical for healthy macrophage functions as they preserve their epigenetic chromatin state. Non-oscillatory NFκB is more likely to alter the macrophage-characteristic chromatin state and lead to altered, disease-associated gene expression. Further, while oscillations are pervasive, their duration is modulated by different stimuli, allowing for differential, stimulus-specific gene expression programs. Together, the proposed studies will substantially contribute to our understanding of how NFκB dynamic control determines physiological and pathological gene expression programs.