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Role of CMPK2 in Bioenergetic and Metabolic Adaptation

Award Number: R01AI192777
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: 05/05/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Role of CMPK2 in Bioenergetic and Metabolic Adaptation - SUMMARY Metabolic adaptation is recognized as a critical step for regulating macrophage function during inflammation onset and resolution. Metabolic dysfunction in macrophages leads to devastating outcomes including persistent infections, and chronic inflammatory and autoimmune disorders. While significant progress has been made in understanding how metabolism drives macrophage activation, and evidence show that targeting metabolic routes reappoints uncontrolled inflammation, the understanding of how mitochondrial proteins and mtDNA replication participate in bioenergetic and metabolic adaptation in activated macrophages remains incomplete. In this project, we are establishing a new role for CMPK2, a mitochondrial cytidine/uridine monophosphate kinase involved in mtDNA synthesis and the anti-viral nucleotide analog ddhCTP, in metabolic and bioenergetic adaptation during macrophage activation. Our compelling preliminary data support the overarching premise that the strong induction of CMPK2 by danger signals upholds a proinflammatory phenotype by enabling bioenergetic and metabolic adaptation. We hypothesize that CMPK2-dependent mtDNA synthesis sustains ATP production through both OxPhos and glucose oxidation, aiding metabolic adaptation and accumulating glycolysis and TCA cycle metabolites key for the inflammatory response (lactate, succinate, itaconate). CMPK2-driven mtDNA synthesis maintains mitochondrial dynamics and fuel flexibility that support residual OxPhos and ATP output (Aim 1). This process preserves NADH and NAD+ balances needed to support glycolysis. Hence, CMPK2 ablation, which further reduces NAD+, inhibits glycolysis and diverts glucose towards the PPP pathway producing NADPH required to catabolize arginine into nitric oxide, which may further restrain glycolysis through S- nitrosylation of GAPDH (and/or other metabolic enzymes) (Aim 2). We will use myeloid-specific CMPK2 knockout mice, primary mouse and human macrophages, genetic (dPCR, RNAseq), bioenergetic (Seahorse Bioanalyzer), and metabolic (GC/MS, stable isotope tracing, 1D 1H-NMR), and imaging (live cell and lattice sheet microscopy (LLSM) and MitoTNT) tools to study mitochondrial and metabolic adaptation during the induction and resolution of the inflammatory response in vitro and in vivo. Together, these studies will broaden our understanding of the contribution of CMPK2 induction and mtDNA synthesis to metabolic adaptation in macrophages and other cells with enhanced CMPK2 expression. We are optimistic that these findings will contribute to the development of innovative strategies to regulate innate response control, laying the foundation for future immunometabolic therapies. The discoveries generated in this project will have broad implications for human conditions linked to inflammation driven by macrophages and other immune cells.


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 = $722,451 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	5/4/2026	NEW	$722,451
														Subtotal = $722,451

Grand Total All Awards = $722,451

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Role of CMPK2 in Bioenergetic and Metabolic Adaptation

Award Number: R01AI192777

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: 05/05/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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