# PGC-1 alpha in Lung Immune Response

> **NIH VA I01** · OMAHA VA  MEDICAL CENTER · 2024 · —

## Abstract

Pseudomonas aeruginosa is a major health challenge that causes recalcitrant multi-drug resistant
infections, especially in immunocompromised and hospitalized patients. Multi- and pan-drug resistant strains of
P. aeruginosa are increasing threats that contribute to high mortality in these patients (1-3). Hence, there is an
urgent need to develop new strategies to combat P. aeruginosa and other resistant pathogens. The pathogenic
profile of P. aeruginosa is related to its ability to secrete a variety of virulence factors. Novel therapeutic
strategies that strengthen the ability of the host would enhance immune defenses and improve outcomes. Over
the previous funding cycle, we elucidated the mechanisms by which lipid mediators regulate the lung’s innate
immune responses to P. aeruginosa virulence factors (5-8). We discovered that 15d-PGJ2, stimulates host
responses to P. aeruginosa through peroxisome proliferator-activated receptor gamma (PPAR), a ligand-
activated transcription factor (9-11). Further, we showed that PPAR agonists inhibit P. aeruginosa biofilm
formation and enhance bacterial clearance from the lungs. Studies to determine the mechanisms by with
PPAR modulates host response in epithelial cells revealed that P. aeruginosa : 1) inhibit paraoxanase-2, a
key mitochondrial enzyme that hydrolyses C12-HSL (12, 13), and 2) inhibit PPAR coactivator 1-alpha (PGC-
1α) and mitochondrial transcription factor A (TFAM), disrupting mitochondrial biogenesis and bioenergetics
(14,15). These mitochondrial derangements impaired epithelial ATP production, increased reactive oxygen
species (ROS), and enhanced glycolysis to disrupt epithelial barrier integrity and immune function. Most
importantly, our new data show that PGC-1α overexpression or activation rescues mitochondrial bioenergetics
and epithelial junctional integrity preventing bacterial transmigration in vitro and enhancing clearance of
bacteria in lungs of mice infected with P. aeruginosa in vivo. Therefore, we hypothesize that P. aeruginosa
evades host defenses by disrupting mitochondrial biogenesis, epithelial barrier integrity, and immune
function. Strategies to restore PGC-1α provide a novel therapeutic approach to stimulate mitochondrial
biogenesis and enhance immune function in P. aeruginosa lung infections. To test this hypothesis, we propose
three specific aims: 1) Investigate the molecular mechanisms by which P. aeruginosa attenuates PGC-1α in
host lung epithelial cells.2) Elucidate how attenuation of PGC-1α compromises host epithelial barrier and
immune function in response to P. aeruginosa. 3) Define the impact of rescuing PGC-1α activation and
mitochondrial biogenesis in P. aeruginosa pneumonia in vivo. The PI’s investigative team provides needed and
complementary expertise to advance this paradigm-shifting work focused on enhancing host resistance to
invasive pathogens. Successful completion of these integrated studies will provide new insights into the
molecular pathogenesis of...

## Key facts

- **NIH application ID:** 10721343
- **Project number:** 5I01BX001786-11
- **Recipient organization:** OMAHA VA  MEDICAL CENTER
- **Principal Investigator:** Ruxana T Sadikot
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-07-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721343

## Citation

> US National Institutes of Health, RePORTER application 10721343, PGC-1 alpha in Lung Immune Response (5I01BX001786-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10721343. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*