# Development of dmPGE2 and Bcl-xl-targeting senolytics as medical countermeasures for H-ARS and DEARE

> **NIH NIH U19** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $238,276

## Abstract

The growing threat of terrorist events involving radiation, as well as the potential for radiation accidents,
underscores the need for effective medical countermeasures (MCM) against radiation. The blood-forming system
is the most sensitive tissue to radiation, resulting in the hematopoietic acute radiation syndrome (H-ARS) after
high dose radiation exposure and death from infection and/or bleeding if untreated. Survivors of H-ARS suffer
later in life by the delayed effects of acute radiation exposure (DEARE), a number of chronic illnesses affecting
multiple organ systems. To date, Neupogen (granulocyte-colony stimulating factor, G-CSF), Neulasta
(pegylated-G-CSF), and Leukine® (GM-CSF) are the only MCM approved by the FDA for treatment of H-ARS,
and will be given as first-line treatments for individuals exposed to high dose radiation. This proposal brings
together uniquely qualified investigators with a long-term productive collaboration studying the efficacy of 16,16
dimethyl prostaglandin E2 (dmPGE2) in H-ARS and DEARE and hematopoietic regeneration. Dr. Orschell is a
radiobiologist and experimental hematologist who developed and validated models of H-ARS in mice of all ages
and strains. Dr. Pelus is a leader in hematopoietic stem cell biology and eicosanoid biology. Together, the Co-
PIs have shown that a single dose of dmPGE2 given up to 30hr after lethal radiation exposure, significantly
enhanced 30 day survival and hematopoietic recovery. With collaborator Dr. Miller, the team has shown that
dmPGE2 given as a radioprotectant before irradiation provides significant alleviation of hematopoietic, lymphoid,
cardiac and renal DEARE. However, dmPGE2, nor any of the three licensed MCM listed above, have shown
efficacy for DEARE when given as radiomitigators (after irradiation). Collaborator Dr. Zhou, an expert in DEARE
and senescence, has recently joined the group to test the ability of novel Bcl-xl-targeting senolytic agents to
alleviate DEARE in mice treated with dmPGE2 as a radiomitigator. The PIs will test the hypothesis that dmPGE2
fulfills all the requirements of an ideal MCM for H-ARS and when used in conjunction with senolytics in survivors,
embodies an effective strategy to mitigate both the acute and delayed toxicities of lethal radiation exposure. The
following Specific Aims will be tested: 1a) determine the optimal dosing regimen and delayed administration
schedule of dmPGE2 in well-established young adult, pediatric, and Jackson Diversity Outbred mouse models
of H-ARS, and b) perform PK of dmPGE2 in primates, 2) establish the transcriptional mechanisms affected when
dmPGE2 is administered as a radiomitigator 24hr after exposure and identify the target hematopoietic cell
population(s), and 3) explore combinatorial activity of dmPGE2 with: a) RP-1, a novel non-lipid LPA2 receptor
agonist (with Dr. Tigyi), b) Neupogen®, and c) a novel senolytic MCM (with Dr. Zhou) to determine if co-
administration provides superior efficacy in H-ARS an...

## Key facts

- **NIH application ID:** 10194367
- **Project number:** 5U19AI150574-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** CHRISTIE M Orschell
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $238,276
- **Award type:** 5
- **Project period:** 2020-06-16 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10194367

## Citation

> US National Institutes of Health, RePORTER application 10194367, Development of dmPGE2 and Bcl-xl-targeting senolytics as medical countermeasures for H-ARS and DEARE (5U19AI150574-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10194367. Licensed CC0.

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