# Lung Injury Repair by Regulatory T cell LGP2

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $409,375

## Abstract

PROJECT SUMMARY
Lung Injury Repair by Regulatory T cell LGP2
The overall objective of this R01 proposal is to investigate mechanisms that direct the immune system to resolve
severe acute lung inflammation. The team for this proposal, comprising expert investigators from two leading
universities, has designed a research strategy that will validate new therapeutic targets acute respiratory distress
syndrome (ARDS), which is a devastating condition that causes significant morbidity and mortality in the U.S.
Despite thorough investigation into the injury and inflammation that drive ARDS, no targeted therapies promote
its resolution. Regulatory T cells (Tregs) — a subset of CD4+ lymphocytes that suppress exuberant immune
system activation—resolve inflammation in mouse models of lung injury. However, the mechanisms that promote
Treg function following lung injury remain unknown. Preliminary data identified in Tregs the Lgp2 locus, which
encodes the immune regulatory protein LGP2, as a novel site that augments Treg responses to inflammation.
DNA methylation at this site is dynamic and contributes to repression of the Dhx58 locus following lung injury.
Thus, the hypothesis of Treg DNA hypomethylation at the Lgp2 locus will increase LGP2 protein levels, enhance
Treg pro-repair function, and promote resolution of acute lung inflammation. To test this hypothesis the following
Specific Aims are proposed: 1. Define the role of the Dnmt-Uhrf1 complex in promoting methylation of Lgp2 in
Tregs during ALI resolution; 2. Determine the role of LGP2 in regulating Treg pro-repair function during ALI
resolution; and 3. Evaluate the role of JHU848 in promoting Treg-mediated ALI resolution. To specifically test
our hypothesis we will employ transgenic mice including strains with Dhx58 deficiency as well as Treg-specific
Uhrf1 deficiency. We have also designed an RNA interference strategy to acutely knock down Dhx58 in cultured
Tregs and boost Dhx58 expression with mutant DNA plasmids. Major methods for this proposal include
established mouse models of acute lung injury (intratracheal lipopolysaccharide and Pseudomonas aeruginosa
administration), DNA methylation sequencing techniques, and multicolor flow cytometry. Accomplishment of
these aims will uncover mechanisms controlling Treg function during resolution of acute lung injury that could be
translated for therapeutic benefit in ARDS.

## Key facts

- **NIH application ID:** 9999662
- **Project number:** 5R01HL131812-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Franco Rafael D'Alessio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999662

## Citation

> US National Institutes of Health, RePORTER application 9999662, Lung Injury Repair by Regulatory T cell LGP2 (5R01HL131812-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9999662. Licensed CC0.

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