# Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction

> **NIH NIH U01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2021 · $565,254

## Abstract

PROJECT DESCRIPTION: This U01 proposal is intended to investigate the pathobiology of radiation-
induced vascular endothelial cell (EC) injury and elucidate the mechanisms responsible for its attenuation by
human ghrelin. Radiological incidents can cause severe and widespread organ damage, of which
endothelial injury is a key component. We have demonstrated that ghrelin administration starting at 24 h
after total body irradiation (TBI) doubled the survival rate of rodents exposed to TBI. Ghrelin attenuated
endothelial activation and leakage in the lungs of irradiated mice and in irradiated human umbilical vein EC
(HUVEC) monolayers. For the first time, we discovered pyroptosis, a new mechanism of cell death, in the
lungs of mice exposed to TBI and in irradiated HUVECs. Serum levels of the novel inflammatory mediator
cold-inducible RNA-binding protein (CIRP) were elevated in TBI mice and reduced by ghrelin. When
exposed to recombinant murine CIRP, mouse lung vascular ECs underwent pyroptosis associated with
NLRP3 inflammasome assembly and NAD(P)H oxidase activation. Ghrelin also decreased radiation-
induced production of reactive oxygen species in HUVECs. Based on these novel findings, we hypothesize
that ghrelin mitigates radiation-induced endothelial injury by inhibiting CIRP-mediated EC pyroptosis. We
will determine ghrelin’s beneficial effects on endothelial integrity after irradiation, examine ghrelin’s effects
on radiation-induced EC pyroptosis and the role of CIRP, and evaluate the long-term effects of ghrelin
treatment on radiation-induced EC injury in mice after TBI. These proposed studies will further confirm
ghrelin’s beneficial effects on radiation injury to vascular ECs and establish CIRP-induced EC pyroptosis as
a novel mechanism of radiation-induced injury. This information will support the preclinical and clinical
development of human ghrelin towards its FDA approval as a novel and effective radiation medical
countermeasure.

## Key facts

- **NIH application ID:** 10159192
- **Project number:** 5U01AI133655-05
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Max Brenner
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $565,254
- **Award type:** 5
- **Project period:** 2017-06-07 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159192

## Citation

> US National Institutes of Health, RePORTER application 10159192, Mechanisms of Radiation-induced Vascular Endothelial Cell Injury and Its Correction (5U01AI133655-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10159192. Licensed CC0.

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