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Investigating the crosstalk between DNA damage and innate immune signaling networks in macrophages

Award Number: R16GM159931
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Investigating the crosstalk between DNA damage and innate immune signaling networks in macrophages - PROJECT SUMMARY Innate immune cells sense and respond to bacterial pathogens through pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns. Coordinated responses to the infection depend on the integration of multiple signaling networks that drive innate immune transcriptional responses. In macrophages, a critical innate immune cell type that is among the first to respond to invading bacteria, signaling downstream of PRRs leads to activation of key transcription factor nuclear factor kappa B (NF-κB), which drives the production of numerous pro-inflammatory mediators that shape the immune response to infection. Among these mediators are reactive oxygen and nitrogen intermediates (ROI/RNI) that eradicate or disable bacterial pathogens. These intermediates are highly genotoxic, however, and can therefore also cause injury to host cells. As such, we recently established that RNI produced during bacterial infection induce DNA double-strand breaks (DSBs) in macrophage genomic DNA. These DSBs activate a multifactorial DNA damage response (DDR) that regulates macrophage transcriptional responses during infection with intracellular bacterium Listeria monocytogenes (L.m.). Notably, both PRR and DDR signaling lead to NF-κB activation through regulatory protein NF-κB essential modulator, or NEMO. Following DNA injury, NEMO is post-translationally modified (PTM) in the nucleus. Importantly, these PTMs are unique to NF-κB activation elicited by DNA damage. Potential crosstalk between extracellular (e.g. PRR) and intracellular (e.g. DNA damage) signals, converging on NF-κB activation, has not been substantively investigated and thus, is a key knowledge gap. We find that in L.m.-infected macrophages, DDR kinase DNA-PKcs regulates the expression of several genes that are known NF-κB transcriptional targets. Thus, we hypothesize that during bacterial infection, NF-κB activity is modulated by both DNA damage-induced DNA-PKcs signaling and PRR signaling in macrophages to synergistically drive L.m.-elicited transcriptional responses. To test this, we will investigate the impact of DNA-PKcs deficiency on NF-κB activity and global chromatin binding during infection with L.m. Using a NEMO mutant that cannot be phosphorylated downstream of DNA damage, we will then determine the impact of inactivating DDR-induced NF-κB activation on macrophage transcriptional responses during L.m. infection. Aberrant NF-κB activity can lead to a range of human pathologies, from immunodeficiency to hyperinflammation to cancer. Indeed, NF-κB activation downstream of DNA injury specifically is known to be a driver of various neoplasms. Thus, a substantive understanding of the interaction among multiple signaling pathways that converge on NF-κB activation will inform the design of rational therapeutics to combat pathologies caused by dysregulated NF-κB activity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $184,375 )
2026	2026	CALIFORNIA STATE UNIVERSITY, EAST BAY FOUNDATION, INC.	25800 CARLOS BEE BLVD	HAYWARD	CA	94542	ALAMEDA	USA	Biomedical Research and Research Training	000	2	5/28/2026	NON-COMPETING CONTINUATION	$184,375
														Subtotal = $184,375

Issue Date FY: 2025 ( Subtotal = $184,375 )
2025	2025	CALIFORNIA STATE UNIVERSITY, EAST BAY FOUNDATION, INC.	25800 CARLOS BEE BLVD	HAYWARD	CA	94542	ALAMEDA	USA	Biomedical Research and Research Training	000	1	8/20/2025	NEW	$184,375
														Subtotal = $184,375

Grand Total All Awards = $368,750

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Investigating the crosstalk between DNA damage and innate immune signaling networks in macrophages

Award Number: R16GM159931

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/20/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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