# E3 Ligase-Mediated Immunosuppression in Acute Lung Injury

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $753,264

## Abstract

Abstract
Acute respiratory Distress Syndrome (ARDS) is a devastating disorder with a high mortality. Prior studies have
focused mainly on its hyper-inflammatory state and yet anti-inflammatories for ARDS have not shown benefit.
Mounting data suggest that immune suppression partakes in this disorder, the molecular mechanisms of which
remain unclear. This application investigates a unique molecular model whereby we discovered an
immunosuppressive protein called Fbxo24, that disposes of a key transcriptional protein, called ELF2, that is
indispensable for critical cytoprotective functions of epithelia including innate immune function and preservation
of cell proliferative activity. By targeting the C-terminal molecular signature present in Fbxo24, we designed,
synthesized, and tested a novel small molecule Fbxo24 antagonist that restores ELF2 levels and innate immune
responses in ARDS models. Our hypothesis is that Fbxo24, in part, mediates immunosuppression in
experimental ARDS through ubiquitin-mediated degradation of ELF2, a protein essential for host
epithelial cell innate immune and reparative responses. Hence, in this application we will first elucidate if
Fbxo24 targets ELF2 for its ubiquitin-mediated proteolysis in experimental ARDS (Aim 1). We will specifically
elucidate the biologic relevance of reduced Fbxo24 levels in preclinical models of ARDS as an immune
suppressor using gene transfer in our Fbxo24 knockout mice and the mechanisms by which Fbxo24 mediates
ELF2 ubiquitination and degradation in a site-specific manner. Next, we will optimize the pharmacologic design
and test a novel small molecule that exhibits distinct, and yet complementary cytoprotective and innate immune
properties in ARDS models (Aim 2). We will employ complementary murine and 2-hit models of immune
suppression and an ex vivo isolated human lung system. These studies will provide a new pathobiologic model
of epithelial injury that will serve as a platform for generating small molecule modulators that optimize cellular
repair and modulate immunity in subjects with severe critical illness.

## Key facts

- **NIH application ID:** 10976089
- **Project number:** 2R01HL096376-10A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Rama K Mallampalli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $753,264
- **Award type:** 2
- **Project period:** 2010-02-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10976089

## Citation

> US National Institutes of Health, RePORTER application 10976089, E3 Ligase-Mediated Immunosuppression in Acute Lung Injury (2R01HL096376-10A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10976089. Licensed CC0.

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