# Sphingolipids as Novel Therapeutic Targets in Radiation Lung Injury

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $399,750

## Abstract

ABSTRACT
Radiation-induced lung injury (RILI) is a common complication in patients administered thoracic radiotherapy
that is associated with significant morbidity and mortality and for which targeted therapies currently do not
exist. Although the molecular etiology is poorly understood, we previously characterized a murine model of
RILI in which alterations in lung barrier integrity surfaced as a potentially important pathobiological event and
genome-wide lung mRNA levels identified dysregulation of sphingolipid metabolic pathway genes. We
subsequently confirmed sphingolipid involvement in murine RILI by radiation-induced increases in lung
expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to
sphingosine 1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage fluid, and
lung tissue. Moreover, mice with a targeted deletion of SphK1 (SphK1-/-) or with reduced expression of S1P
receptors (S1PR1+/-, S1PR2-/-, and S1PR3-/-) exhibited marked RILI susceptibility and we observed RILI
protection conferred by the S1P analog, (S)-FTY720-phosphonate (Tys). As these findings support an
important role for S1P signaling in RILI we hypothesize specific molecular mechanisms involved in
sphingolipid-mediated responses to radiation may serve as novel therapeutic targets. This hypothesis serves
as the basis for the current proposal which is comprised of three specific aims. One potential molecule of
interest in is TRPM2 (transient receptor potential melastatin-2), an oxidant sensitive, non-selective, cation
channel expressed in the lung endothelium that is known to regulate endothelial cell (EC) permeability and
cellular responses to radiation injury. As our preliminary data implicate TRPM2 as a mediator of both lung EC
barrier regulation by S1P and murine RILI susceptibility, Specific Aim #1 will examine the role of TRPM2 in
sphingolipid-mediated lung responses to radiation and its potential viability as a therapeutic target in RILI.
Separately, we have also identified differential RILI responses mediated by the deubiquitinating enzyme,
UCHL1 (ubiquitin carboxyl-terminal esterase L1) and we have confirmed SphK1 ubiquitination regulated by
UCHL1 as well UCHL1 regulation by TRPM2. In Specific Aim #2 we will extend these findings to fully define
the role of UCHL1 in the regulation of sphingolipids affected by radiation in vivo and in vitro. Finally, in Specific
Aim #3 we will study epigenetic events modulated by sphingolipids in response to radiation and characterize
specific genes of interest differentially regulated in this context, an entirely novel area of investigation
supported by our preliminary data confirming radiation-induced SphK phosphorylation associated with histone
acetylation in human lung EC. Collectively, these studies will yield new insights into mechanisms of
sphingolipid signaling, mediators of sphingolipid regulation and downstream epigenetic modifications mediated
by sphing...

## Key facts

- **NIH application ID:** 10138008
- **Project number:** 5R01HL147942-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** JEFFREY R JACOBSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,750
- **Award type:** 5
- **Project period:** 2020-04-05 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138008

## Citation

> US National Institutes of Health, RePORTER application 10138008, Sphingolipids as Novel Therapeutic Targets in Radiation Lung Injury (5R01HL147942-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10138008. Licensed CC0.

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