Wednesday, December 31, 2025 12/31/2025

NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation

Award Number: R37AI043477
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: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation - ABSTRACT In the past three years, we made great progress in understanding the role of mitochondrial (mt) DNA metabolism in NLRP3 inflammasome activation. Importantly, we found that NLRP3 itself is activated on binding of oxidized (Ox) mtDNA, whose generation depends on new mtDNA synthesis which is stimulated on TLR engagement. TLR signaling results in induction of CMPK2, which catalyzes the rate limiting step in the biosynthesis of dCTP, a precursor for mtDNA synthesis. We recently discovered that Ox-mtDNA needs to be cleaved by the endonuclease Fen1 and transported/leaked to the cytoplasm, where NLRP3 is located, via the mitochondrial inner membrane (MIM) MPTP pore and the mitochondrial outer membrane (MOM) VDAC channel. Macrophage exposure to different NLRP3 activators results in rapid Ca2+ influx into mitochondria, as well as perturbations to the electron transfer chain that result in mtROS production. Whereas Ca2+ influx into mitochondria leads to pore and channel opening, mROS lead to oxidation of newly synthesized mtDNA before it is cleaved by Fen1 to 600 bp fragments that leak into the cytoplasm. Another important player in mtDNA metabolism is OGG1, a baseexcision repair enzyme that removes oxidized deoxyguanosine from mtDNA, whose insufficiency greatly increases Alzheimer’s disease (AD) risk. We found that OGG1 ablation in macrophages enhances NLRP3 inflammasome activation, whereas mitochondrially targeted OGG1 inhibits NLRP3 inflammasome activation. We therefore we plan to study the involvement of mtDNA metabolism in AD pathogenesis, using the accelerated 5xFAD model crossed with ApoE4 knockin mutant mice. These mice will be analyzed over the course of disease development and progression for CMPK2, NLRP3, ASC, caspase-1, OGG1 and Fen1 expression and presence of Ox-mtDNA and mature IL-1β in their circulation, cerebrospinal fluid, and brain tissue homogenates. Microglia (MG) from these mice will be isolated at different time points and analyzed for presence of ASC specs, indicative of NLRP3 inflammasome assembly, presence of cytosolic mtDNA and signs of MPTP opening and VDAC oligomerization. We will determine whether crossing of 5xFAD/ApoE4 mice with mtOgg1Tg mice results in reduced abundance of cytoplasmic mtDNA, Ox-mtDNA and IL-1β and whether this parallels the amelioration of neurodegeneration and cognitive loss. Conversely, we will delete OGG1 in MG of 5xFAD/ApoE4 mice to determine whether this results in accelerated development of neurodegeneration. We will also cross 5xFAD/ApoE4 and Cmpk2ΔMG mice, in which the Cmpk2 gene was ablated with MG-specific Cre and determine whether this also results in disease amelioration. According to the results of the above experiments, 5xFAD/ApoE4 mice will be treated with newly developed CMPK2 and Fen1 inhibitors and will be evaluated for attenuation of neurodegeneration and cognitive loss. Human AD tissue will also be examined for CMPK2 and Fen1 expression as well as presence of ASC specs and Ox-mtDNA. These studies will provide us with a comprehensive view of mtDNA metabolism in AD and will determine whether some of the key steps in the NLRP3 activation pathway, we had identified, are suitable for therapeutic intervention. In addition to AD, we will assess the contribution of mtDNA metabolism to osteoarthritis (OA), a chronic degenerative disease that unlike rheumatoid arthritis does not respond to anti-TNF drugs. It has been suggested that NLRP3 activation by hydroxyapatite microcrystals is the trigger for OA. We are currently working on the establishment of a robust OA model and when it is ready, we will test the effect of CMPK2 and Fen1 inhibition, as well as mtOGG1 expression, on disease progression and severity. We will also determine whether mouse and human OA specimens show the same perturbations in mtDNA metabolism discussed above. As IL-1β neutralizing antibody was found to reduce the incidence of lung adenocarcinoma (LUAC) in smokers, w


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 = $73,885 )
2026	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	29	12/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$389,397
2026	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	28	12/18/2025	NON-COMPETING CONTINUATION	-$315,512
														Subtotal = $73,885

Issue Date FY: 2025 ( Subtotal = $600,599 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	28	6/4/2025	NON-COMPETING CONTINUATION	$600,599
2025	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	26	1/19/2025	EXTENSION WITH OR WITHOUT FUNDS	$243,579
2025	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	25	1/19/2025	NON-COMPETING CONTINUATION	-$243,579
														Subtotal = $600,599

Issue Date FY: 2024 ( Subtotal = $600,599 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	27	5/27/2024	NON-COMPETING CONTINUATION	$600,599
2024	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	24	1/31/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $600,599

Issue Date FY: 2023 ( Subtotal = $600,599 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	26	1/25/2023	EXTENSION WITH OR WITHOUT FUNDS	$600,599
														Subtotal = $600,599

Issue Date FY: 2022 ( Subtotal = $590,745 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	25	5/11/2022	NON-COMPETING CONTINUATION	$590,745
														Subtotal = $590,745

Issue Date FY: 2021 ( Subtotal = $624,533 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	24	5/26/2021	SUPPLEMENT FOR EXPANSION	$33,788
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	24	5/5/2021	NON-COMPETING CONTINUATION	$590,745
														Subtotal = $624,533

Issue Date FY: 2020 ( Subtotal = $962,400 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	23	5/4/2020	NON-COMPETING CONTINUATION	$590,745
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	23	7/29/2020	SUPPLEMENT FOR EXPANSION	$371,655
														Subtotal = $962,400

Issue Date FY: 2019 ( Subtotal = $710,961 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	22	7/11/2019	NON-COMPETING CONTINUATION	$590,745
2019	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	21	10/30/2018	COMPETING CONTINUATION	$120,216
														Subtotal = $710,961

Issue Date FY: 2018 ( Subtotal = $590,745 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	21	4/30/2018	COMPETING CONTINUATION	$590,745
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	21	7/16/2018	COMPETING CONTINUATION	$0
														Subtotal = $590,745

Grand Total All Awards = $5,355,066

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NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation

Award Number: R37AI043477

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: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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