# Examining the role of TRMT1 and tRNA methylation in acute lung injury and ARDS

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $517,676

## Abstract

Abstract:
 ARDS accounts for one in ten intensive care unit (ICU) admissions. Mortality in ARDS is estimated at 30 –
50%. Decades of clinical trials have failed to identify targeted pharmacotherapeutics that significantly impact
disease course. New insights are needed to broaden our understanding of the underlying mechanisms that
lead to ARDS to promote the development of novel therapeutics.
 Transfer RNA (tRNA) constitutes 10 – 20% of the total cellular RNA content. Although classically thought of
passive translational machinery, more recent studies show that tRNA can be dynamically regulated in
response to the environment. The post-translation modification of tRNA by methylation is one mechanism by
which tRNAs respond to cellular stress. Methylation of tRNAs can alter translation, change the distinction
between ‘self’ and ‘non-self’, and protect tRNAs from fragmentation. Despite this, the role of tRNAs in infection
and critical illness is unknown. We identified a methyltransferase enzyme, termed TRMT1 that is upregulated
in the human lung in response to infection. We also find that the methylation of tRNA by TRMT1 is altered in
response to inflammatory stimuli. Our preliminary data suggest that the TRMT1 is vital for macrophage viability
and host defense in infection, and for maintaining cytokine responses. This application focuses on the role of
the TRMT1 in acute lung injury and the investigation of tRNA biology, unexplored territory in ARDS and critical
care illnesses.
 During the execution of these studies, we will examine how myeloid TRMT1 contributes to
immunopathology in experimental lung injury. We will determine how TRMT1 alters inflammatory signaling and
regulates cell death in vitro and in vivo. To examine the mechanistic role of TRMT1, we will measure the
methylation of tRNA in response to inflammatory stimuli and the production of tRNA fragments. To further
explore the regulation of TRMT1, we will examine how subcellular trafficking of TRMT1 differentially regulates
cytoplasmic and mitochondrial tRNA methylation and how this alters the inflammatory response. Finally,
because cellular concentrations of TRMT1 protein may be crucial in regulating macrophage behavior and
viability we will examine the E3 ligase mediated ubiquitination and degradation of TRMT1.
 These studies will be the first to elucidate the role of TRMT1 in acute lung injury. In addition, these studies
will provide new insight into the role tRNA methylation in lung injury. The execution of these studies will provide
significant mechanistic and biological advances in the field of acute lung injury and ARDS and lead to novel
interventional targets for therapeutics.

## Key facts

- **NIH application ID:** 10857211
- **Project number:** 5R01HL169586-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** James David Londino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $517,676
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10857211

## Citation

> US National Institutes of Health, RePORTER application 10857211, Examining the role of TRMT1 and tRNA methylation in acute lung injury and ARDS (5R01HL169586-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10857211. Licensed CC0.

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