Targeting the NRF2 axis to reduce lung immunopathology in polg-related mitochondrial disease

Ended Project Grant Awarded Last action

Award ID
F31AI179168
Recipient
Awarding agency
Obligated
$243,196

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date
Place of performance
Bryan, TX 77807, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Transactions

Action Obligated Date
Amendment -$6,146
Amendment -$25,625
Amendment -$25,625
Amendment $564
Amendment $564
Amendment $37,797
Amendment $37,797
Amendment $37,797
Amendment $1,280
Amendment $1,280
Amendment $36,288
Amendment $0
Amendment $36,288
Amendment $36,288
Amendment $0
Amendment $36,288
Original award $0
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Quick answers

Who received award F31AI179168?

F31AI179168 was awarded to Texas A & M University System Health Science Center by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 1, 2024.

How much is award F31AI179168 worth?

$243,196 has been obligated on F31AI179168.

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