# Targeting linear ubiquitination to attenuate inflammation and promote repair after IAV infection

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $687,186

## Abstract

PROJECT SUMMARY
The central hypothesis of this project is to consider the persistence of respiratory failure and the development
of multiple organ dysfunction in patients with ARDS as a failure of normal mechanisms of inflammation
resolution and lung repair. This hypothesis is clinically supported by a recent analysis of patients enrolled in
the ARDSnet where a “hyerinflammatory” endotype of ARDS was associated with poor clinical outcomes
including death. The expression of many genes encoding inflammatory cytokines is regulated by the
transcription factor NF-κB. Hence, understanding how NF-κB activity is controlled over the course of lung
injury and repair is likely to provide mechanistic insights into the pathobiology of successful or failed lung repair
after injury.
The Linear Ubiquitin Assembly Complex (LUBAC) is an E3 ubiquitin ligase that performs Met-1 ubiquitination
necessary for NF-κB activation. In preliminary experiments, we observed that epithelial specific deletion of a
modulatory component of LUBAC (HOIL-1L) prevents NF-κB signaling and improves outcomes in a murine
model of influenza A virus infection. We present additional preliminary data that support our hypothesis that
LUBAC promotes persistent NF-κB signaling in the alveolar epithelium and monocyte-derived alveolar
macrophages to inhibit lung repair after influenza A induced lung injury.
Specific Aim 1. To determine whether inhibiting LUBAC-mediated NF-κB activation in the lung
epithelium during recovery from influenza A infection accelerates lung repair. We will perform timed
experiments in which we will genetically inhibit LUBAC mediated NF-κB signaling during recovery from
influenza A infection and use complementary physiologic and molecular techniques to measure lung repair.
Specific Aim 2. To determine whether inhibition of LUBAC mediated NF-κB activation in the lung
epithelium directs reparative phenotypes in monocyte-derived macrophages. We will determine whether
the inflammatory phenotype of these cells is driven by the changing microenvironment—specifically the lung
epithelium, or whether these changes are cell autonomous within the macrophage.
Specific Aim 3. To determine whether increased expression of NF-κB dependent inflammatory genes in
alveolar macrophages from patients with severe pneumonia is associated with adverse clinical
outcomes. We will take advantage of the infrastructure provided by the Successful Clinical Response in
Pneumonia Therapy (SCRIPT) trial to determine whether there is an association between the expression of
NF-κB target genes in alveolar macrophages and clinical outcomes.

## Key facts

- **NIH application ID:** 10072567
- **Project number:** 1R01HL154686-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** GR Scott Budinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $687,186
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072567

## Citation

> US National Institutes of Health, RePORTER application 10072567, Targeting linear ubiquitination to attenuate inflammation and promote repair after IAV infection (1R01HL154686-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072567. Licensed CC0.

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