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Targeting the Nrf2 axis to reduce lung immunopathology in PolG-related mitochondrial disease

Award Number: F31AI179168
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Targeting the Nrf2 axis to reduce lung immunopathology in PolG-related mitochondrial disease - PROJECT SUMMARY Mitochondrial diseases (MD) are a clinically heterogeneous group of disorders caused by respiratory chain dysfunction and metabolic failure. These diseases often result from pathogenic mutations in genes that function in oxidative phosphorylation or mitochondrial DNA (mtDNA) maintenance, are often debilitating, and have limited treatment options with no cures. Environmental exposures, such as microbial infection, appear to exacerbate the stepwise progression of MD. MD patients are also more susceptible to recurrent infections from opportunistic respiratory pathogens including Pseudomonas aeruginosa (PA). Infections can quickly spiral out of control, leading to sepsis and unrestrained inflammatory responses in MD patients. The underlying immune alterations in MD that enhance immunopathology are unclear, constituting a key gap in knowledge that complicates treatment and increases mortality in these patients. Thus, there is a critical need for mechanistic research to advance immune-focused therapies for MD. Mutations in mtDNA polymerase gamma (PolG) represent the most prevalent single-gene cause of MD. Ongoing experiments using a faithful mouse model of PolG-related MD have uncovered novel immune alterations in PolG mutant animals. Notably, PolG mutants exhibit elevated numbers of myeloid immune cells in the lung and increased lung neutrophil infiltration and cytokine production after instillation of bacterial lipopolysaccharide or intranasal delivery of PA. Additional preliminary experiments revealed that PolG mutant macrophages undergo increased pyroptosis after exposure to PA, which is driven by elevated expression and activity of caspase-11. Prior mechanistic studies showed widespread repression of the transcription factor nuclear erythroid 2-related factor 2 (Nrf2) in PolG mutant mice. Nrf2 orchestrates both antioxidant and anti-inflammatory responses. Stabilizing Nrf2 with the FDA-approved drug dimethyl fumarate (DMF) was effective at reducing inflammation in PolG macrophages exposed to live PA. Therefore, this proposal will test the central hypothesis that loss of Nrf2 activity promotes myeloid cell hyperinflammation, lung immunopathology, and increased morbidity and mortality in PolG mutant mice and patients with PolG-related MD. Specific Aim 1 will test the hypothesis that elevated type I interferon (IFN-I) signaling and the subsequent reduction of Nrf2 activity in PolG mutant macrophages promotes hyperinflammatory innate immune signaling and inflammatory cell death via potentiated non-canonical inflammasome activation. Specific Aim 2 tests the hypothesis that hyperinflammatory innate immune responses contribute to acute lung injury during PA infection using a faithful in vivo model of PolG-related MD. Both Aims will incorporate in vitro and in vivo DMF treatments to characterize how Nrf2 stabilization alleviates hyperinflammation and reduces lung pathology during PA infection. This research will fundamentally advance understanding of innate immune defects in a relevant model of MD. It may also lead to the development of innovative Nrf2-based therapies to slow the damaging toll of respiratory infections and lung immunopathology in PolG-related MD or other mitochondrial disorders.


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: 2025 ( Subtotal = $38,361 )
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	2	7/29/2025	NON-COMPETING CONTINUATION	$564
2025	2025	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	2	5/6/2025	NON-COMPETING CONTINUATION	$37,797
														Subtotal = $38,361

Issue Date FY: 2024 ( Subtotal = $37,568 )
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	001	1	3/15/2024	NEW	$0
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	002	1	5/13/2024	NEW	$1,280
2024	2024	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Allergy and Infectious Diseases Research	000	1	3/15/2024	NEW	$36,288
														Subtotal = $37,568

Grand Total All Awards = $75,929

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Targeting the Nrf2 axis to reduce lung immunopathology in PolG-related mitochondrial disease

Award Number: F31AI179168

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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