# The role of epigenetic regulator UHRF1 in stability of induced regulatory T-cell function during influenza A virus-induced lung injury

> **NIH NIH F32** · NORTHWESTERN UNIVERSITY · 2022 · $76,246

## Abstract

PROJECT SUMMARY/ABSTRACT
This proposal for an NRSA Individual Fellowship is centered on two principal goals: 1) afford the candidate the
necessary time and resources required to develop into an independent physician-scientist, and 2) investigate
the mechanisms governing the stability of induced regulatory T cells (iTregs) in experimental influenza viral
pneumonia. The candidate and his mentors have outlined a comprehensive and progressive research plan to
achieve these objectives while laying the foundation for a successful, independent research career. Despite
decades of clinical experience and research, severe viral pneumonia and ARDS remain a leading cause of
morbidity and mortality worldwide. Regulatory T-cells are a subset of CD4+ T-cells critical to maintaining immune
homeostasis and coordinating lung tissue repair after injury. Tregs require stable expression of the Foxp3
transcription factor. Stable, long-lived FoxP3+ Tregs that originate from the thymus are referred to as natural
Tregs (nTregs). In vitro, TGF-β induces transient Foxp3 expression and imparts temporary suppressive function
to naïve CD4+ T-cells, generating cells defined as iTregs. The inherent instability of iTreg phenotype and function
poses a concern for their clinical use as a cellular therapy, as reversion to a CD4+ effector T-cell phenotype
promotes inflammation. The stability of Treg-specific transcriptional programs is known to be regulated by DNA
methylation, a process mediated by DNA methyltransferases and their adapter protein, UHRF1. iTregs
generated from UHRF1-null naïve CD4+ T-cells possess enhanced suppressive function. Hence, we
hypothesize that UHRF1 expression in iTregs destabilizes acquired suppressive and reparative
transcriptional programs, leading to loss of pro-recovery function following viral pneumonia. The long-
term hope of this proposal is to identify determinants of maintenance of transcriptional and functional stability in
iTregs and provide validation for their use as cellular therapy in patients suffering from viral pneumonia-induced
ARDS.
In Specific Aim 1, we will determine whether UHRF1 is necessary to destabilize iTreg suppressive and reparative
transcriptional programs both in vitro and in vivo via tandem RNA-seq and DNA methylation analysis. In Specific
Aim 2, we will determine whether loss of UHRF1 in iTregs is sufficient to promote recovery following viral
pneumonia. We will use cutting-edge techniques for adoptive cell transfer, severity assessment of lung injury,
tamoxifen-based inducible systems in mice, flow cytometry, 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:** 10389878
- **Project number:** 1F32HL162418-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Anthony Joudi
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $76,246
- **Award type:** 1
- **Project period:** 2023-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389878

## Citation

> US National Institutes of Health, RePORTER application 10389878, The role of epigenetic regulator UHRF1 in stability of induced regulatory T-cell function during influenza A virus-induced lung injury (1F32HL162418-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10389878. Licensed CC0.

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