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 NF?B 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 NF?B is activated in response to TLR signaling and that multiple mechanisms converge to regulate NF?B. After developing a live cell microscopy tracking workflow we discovered that contrary to previous notions NF?B dynamics are highly oscillatory. By generating a knockin RelA-Venus mouse, we are able ? for the first time ? measure NF?B dynamics in primary cells revealing oscillations as an intrinsic hallmark of NF?B in healthy macrophages. Based on preliminary studies, we propose to test the hypothesis that NF?B oscillations are critical for healthy macrophage functions as they preserve their epigenetic chromatin state. Non-oscillatory NF?B 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 NF?B dynamic control determines physiological and pathological gene expression programs.

Public Health Relevance

Inflammatory signaling by macrophages in response to pathogens or tissue injury is the key determinant of infectious and non-infectious disease. The key molecular regulator of inflammation, NF?B, is generally oscillatory, yet it is unclear what the role of these oscillations is. Here we test the hypothesis that NF?B oscillations are critical for healthy macrophage functions as they preserve their epigenetic chromatin state, whereas non-oscillatory NF?B is more likely to alter it and lead to altered, disease-associated gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI127864-03
Application #
9589457
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2016-11-17
Project End
2021-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Cheng, Christine S; Behar, Marcelo S; Suryawanshi, Gajendra W et al. (2017) Iterative Modeling Reveals Evidence of Sequential Transcriptional Control Mechanisms. Cell Syst 4:330-343.e5