# A Transcriptional Program Modulating Epithelial Death and Innate Function - Project 1

> **NIH NIH P01** · OHIO STATE UNIVERSITY · 2022 · $431,945

## Abstract

Acute Respiratory Depress Syndrome (ARDS) can be a devastating disorder and prior 
studies have focused mainly on its hyper-inflammatory state. However, mounting data 
suggest that immune suppression partakes in this disorder, the molecular mechanisms of 
which remain unclear. This Project investigates a unique molecular model whereby a lysine 
acetyltransferase termed general control of amino acid synthesis protein 5-like 2 (Gcn5l2), 
normally targeted for its disposal in cells by a ubiquitin E3 ligase subunit, Fbxo24, executes 
alveolar epithelial cell death and suppression of genes involved in innate immunity through 
histone modification. Our hypothesis is that Gcn5l2, normally kept in check by ubiquitin- 
mediated degradation, is an endotoxin-responsive executioner of innate immune suppression 
and epithelial cellular death in experimental ARDS. As a corollary to this hypothesis, we 
propose that Gcn5l2 chemical inhibition will attenuate acetyltransferase activity. Hence, in 
this application we will first elucidate how endotoxin increases Gcn5l2 levels by abrogating its 
Fbxo24 E3 ubiquitin ligase mediated proteolysis in experimental lung injury (Aim 1). We will 
specifically investigate how Fbxo24 targets Gcn5l2 for its degradation using complementary 
in vitro and in vivo genetic models and then evaluate how endotoxin abrogates molecular 
interaction of these partners. Next, we will optimize the pharmacologic design and test a 
novel small molecule that exhibits distinct, and yet complementary immune modulatory and 
cytoprotective properties in 2-hit models of immune suppression and in an ex vivo isolated 
human lung system (Aim 2). These studies will provide a new pathobiologic model of immune 
dysregulation that will serve as a platform for generating small molecule modulators that 
optimize epithelial cell survival and restore host defense in subjects with severe critical 
illness.

## Key facts

- **NIH application ID:** 10399559
- **Project number:** 5P01HL114453-09
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Rama K Mallampalli
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $431,945
- **Award type:** 5
- **Project period:** 2014-01-03 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399559

## Citation

> US National Institutes of Health, RePORTER application 10399559, A Transcriptional Program Modulating Epithelial Death and Innate Function - Project 1 (5P01HL114453-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10399559. Licensed CC0.

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