# Determinants of age-related regulatory T cell function during influenza A virus-induced lung injury.

> **NIH NIH F32** · NORTHWESTERN UNIVERSITY · 2020 · $77,733

## Abstract

PROJECT SUMMARY/ABSTRACT
The broad objectives of this NRSA Individual Postdoctoral Fellowship are two-fold: 1) to mentor the candidate to
become a successful physician-scientist through development of the necessary skills as described in her training
plan, and 2) to uncover the mechanisms that direct regulatory T cells to orchestrate resolution of severe lung
injury throughout the lifespan. The candidate and her mentors have designed a detailed training plan tailored to
the candidate’s specific needs and goals. The proposal focuses on the study of influenza A-induced lung injury,
its clinical counterpart the acute respiratory distress syndrome (ARDS) and how they both disproportionately
affect the elderly population. Despite decades of dedicated research, there are only a few antiviral drugs available
to target the IAV and no specific therapies for ARDS. Regulatory T (Treg) cells have been shown to decrease
inflammation and promote tissue repair through the expression of growth factors, such as amphiregulin, in mouse
models of lung injury. Treg cells also increase in the lungs of patients with ARDS, suggesting that they may play
a role in the human adaptive immune response to lung injury. DNA methylation regulates Treg cell lineage
identity and functional reprogramming throughout the lifespan in response to contextual cues. Whether the age-
related loss of Treg cell pro-recovery function and increased susceptibility to IAV-induced lung injury in aged
hosts is due to changes in their transcriptome or epigenome remains unknown. The focus of this proposal is to
understand how age-acquired DNA methylation patterns lead to changes in Treg cell-specific transcriptional and
functional programs to drive a dysregulated repair response following influenza A virus infection. The long-term
hope of the proposal is to identify novel small molecule- and cell-based therapeutics to control inflammation and
promote tissue repair in our increasingly older population.
In Specific Aim 1, the candidate will determine whether the failure of aged Treg cells to resolve IAV-induced lung
injury results from cell-autonomous or microenvironmentally-driven changes in their transcriptome, epigenome
and function. In Specific Aim 2, the candidate will determine whether aging causes loss of Treg cell pro-repair
function by decreased expression of amphiregulin. We will use standard techniques to assess severity of lung
injury, heterochronic (age mis-matched) adoptive Treg cell transfer, a tamoxifen-based inducible system in mice,
flow cytometry, fluorescence-activated cell sorting, transcriptional profiling with RNA-sequencing and DNA
methylation profiling with modified reduced representation bisulfite sequencing as the primary methods to
support the experimental design of this proposal.

## Key facts

- **NIH application ID:** 9911293
- **Project number:** 1F32HL151127-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Luisa Morales-Nebreda
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $77,733
- **Award type:** 1
- **Project period:** 2020-03-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911293

## Citation

> US National Institutes of Health, RePORTER application 9911293, Determinants of age-related regulatory T cell function during influenza A virus-induced lung injury. (1F32HL151127-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9911293. Licensed CC0.

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