# Modulation of acute lung injury by tristetraprolin

> **NIH NIH P20** · LOUISIANA STATE UNIV A&M COL BATON ROUGE · 2022 · $221,082

## Abstract

Project Summary 
 Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) secondary to sepsis (indirect ALI) is 
a devastating condition that results in a significant morbidity and mortality. Pneumonia and aspiration of gastric 
contents are the two major causes of direct acute lung injury (direct ALI) and it is estimated that 55% of ARDS 
is caused by direct lung injury. Although the pathophysiology of ALI is far from understood, exuberant 
production of pro-inflammatory cytokines and chemokines is known to play a central role. However, it remains 
unclear how these pro-inflammatory mediators are regulated. Tristetraprolin (TTP) is an mRNA binding protein 
that regulates mRNA levels by binding to adenylate-uridylate-rich elements (AREs) in the 3'-untranslated 
regions (3'UTRs) of specific mRNAs resulting in their rapid turnover. Deletion of TTP in mice results in 
systemic inflammation that is mediated by enhanced stability of TTP target mRNAs, such as Tnf. Along the 
same lines, myeloid-specific TTP deficiency results in extreme sensitivity to low dose endotoxin exposure 
resulting in the development of endotoxemia and organ damage. Therefore, we hypothesize that TTP 
mediated post-transcriptional regulation of pro-inflammatory gene expression modulates the pathogenesis of 
ALI; enhancing TTP levels protects from ALI; and that hematopoietic-cell TTP is necessary and sufficient for 
this effect. We will test our hypothesis through two specific aims: In Aim 1, we will test the effect of loss of TTP 
(whole body and myeloid cell-lineage) on the pathogenesis of direct and indirect ALI. In Aim 2, we will test 
whether enhanced expression of TTP protects against the development of ALI and whether hematopoietic cell 
lineage-specific TTP overexpression is necessary and sufficient for protection. The overall goal of the 
proposed research is to improve therapeutic options in ALI (direct and indirect) by providing rationale for drug 
development aimed at cell-specific stabilization/enhanced expression of TTP. Successful completion of these 
studies will advance our understanding of the role of TTP mediated post-transcriptional mechanisms of gene 
expression in regulating the pathogenesis of ALI. The knowledge gained will have potential applications 
towards the identification of TTP-regulated mRNAs as biomarkers of ALI and the development of therapeutic 
interventions to enhance TTP levels for the treatment of ALI.

## Key facts

- **NIH application ID:** 10341067
- **Project number:** 5P20GM130555-04
- **Recipient organization:** LOUISIANA STATE UNIV A&M COL BATON ROUGE
- **Principal Investigator:** Sonika Patial
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $221,082
- **Award type:** 5
- **Project period:** 2019-01-02 → 2022-09-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10341067

## Citation

> US National Institutes of Health, RePORTER application 10341067, Modulation of acute lung injury by tristetraprolin (5P20GM130555-04). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10341067. Licensed CC0.

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