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RNA and DNA sensors in the response of macrophages to ionizing radiation

Award Number: R21AI173847
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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RNA and DNA sensors in the response of macrophages to ionizing radiation - Project Summary Exposure to ionizing radiation (IR) is associated with inflammation due to an upregulation of inflammatory mediators and hyperactivity of the cells responsible for their production. The key immune cells involved in IR- induced inflammation, both as exacerbators and extinguishers, are macrophages (MΦ). Thus, deciphering of the signaling mechanisms responsible for IR-induced activation and polarization of these highly radioresistant cells is important for the identification of therapeutic targets to manage acute and counteract chronic IR- related inflammation. Along with damage-associated molecular patterns, released from irradiated tissues, radiation itself directly impacts MΦ through DNA damage and modulation of transcription that alters the MΦ phenotype. This effect is implemented through the activation of specific DNA and RNA sensors and downstream signaling pathways, resulting in differential expression of type I interferons (IFN-I) and interferon- stimulated genes (ISGs). It is well established that DNA fragments activate the STING/TBK1 pathway, thereby triggering IFN-I expression. However, we recently demonstrated that the cytoplasmic RNA sensors, RIG-I-like receptors (RLRs) and their adaptor protein MAVS, also play a significant role in MΦ activation after IR. We found that activation of the RLR family member MDA5 by double-stranded RNA, due IR-induced transcription of endogenous retroviruses (ERVs), leads to increased expression of IFN-I and inflammation- related genes. This finding generates two important questions that need to be resolved. First, whether the signaling from RLRs is critical for prolonged IR-induced activation of MΦ. Our data that ERV RNA-induced MDA5 signaling and IFN-I expression, in turn, upregulates retroviral transcription, suggests that there is a positive feedback loop for ERV expression that maintains recurrent activation of the RLR-MAVS pathway and thereby inflammatory activation of MΦ. Thus, we propose a time-course study of the involvement of RLR- MAVS signaling, IFN-I response and ERV transcription in the short- and long-term effects of gamma IR using MΦ with knocked out MAVS or IFN-I receptor and in vivo using the wild-type C57BL/6J mice and a MAVS- knockout strain. The second question is whether IR dose influences the impact of RNA sensors versus DNA sensors, with respect to the IR-induced DNA damage. We found that increases in IR dose led to a decline in RLR and MAVS levels, whereas the DNA sensing proteins were consistently upregulated. To test our hypothesis that high IR doses result in DNA sensing pathway activation and a STING-mediated mechanism of IFN-I expression that determines MΦ activation, we will investigate the dose-dependent disruption of RLR- RNA complexes with MAVS, DNA damage and accumulation of DNA fragments and RNA:DNA duplexes to assess their impact on RLR and STING-TBK1 signaling using MΦ cultures and the indicated above mouse strains, along with STING-knockout mice. We expect to identify nucleic acid-related signaling mechanism(s) responsible for the radiation-induced changes in MΦ polarity and their pathological inflammatory activation.


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 = $0 )
2026	2025	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	2/10/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $199,469 )
2025	2025	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	2	4/1/2025	NON-COMPETING CONTINUATION	$199,469
														Subtotal = $199,469

Issue Date FY: 2024 ( Subtotal = $239,363 )
2024	2024	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	1	5/14/2024	NEW	$215,427
2024	2024	THE HENRY M. JACKSON FOUNDATION FOR THE ADVANCEMENT OF MILITARY MEDICINE, INC.	6720A ROCKLEDGE DR	BETHESDA	MD	20817	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	1	9/11/2024	NEW	$23,936
														Subtotal = $239,363

Grand Total All Awards = $438,832

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RNA and DNA sensors in the response of macrophages to ionizing radiation

Award Number: R21AI173847

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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