Development and mechanistic evaluation of an extended-release LPAR2 agonist as a radiation medical countermeasure
Derek Norman
Theoretical and Translational Medicine Division
Dr. Kellermayer Miklós
SE Elméleti Orvostudományi Központ, Hevesy György előadóterem
2026-07-02 15:00:00
Celluláris és molekuláris biofizika
Dr. Tigyi Gábor
Dr. Liliom Károly
Dr. Sáfrány Géza
Dr. Tímár József
Dr. Ella Krisztina
Dr. Tóvári József
The primary drivers of ARS-related mortality are systemic injuries to the
hematopoietic and gastrointestinal systems. Give the lack of robust countermeasures for
GI-ARS, this research focused on the regulatory signaling pathways triggered by
radiation injury. Specifically, we investigated novel pharmacologic approaches to
mitigate cellular injury and improve overall outcomes.
The first component of this research examined pharmacologic activation of
LPAR signaling as a strategy for mitigating gastrointestinal radiation injury. In a murine
model of GI-ARS, treatment with the selective LPAR2 agonist RP-1 significantly
improved survival when administered beginning 24 h after irradiation. RP-1 treatment
also preserved intestinal crypt architecture and increased the number of regenerating
crypts during the critical phase of intestinal epithelial recovery. In vitro experiments
demonstrated that LPAR activation promotes sustained phosphorylation of ERK and
Akt and reduces caspase-mediated apoptosis following irradiation, indicating that LPAR
signaling enhances pro-survival responses during radiation-induced injury.
Development of an extended-release W/O/W ME formulation improved the
pharmacokinetic profile of RP-1 and enabled effective mitigation using a simplified
dosing regimen.
The second component of this thesis investigated the role of IEX-1 in regulating
tissue radiosensitivity. Genetic deletion of IEX-1 resulted in significantly reduced
survival in murine models of both H- and GI-ARS. In addition, small intestinal
enteroids derived from IEX-1 KO mice exhibited delayed growth and altered ERK
signaling kinetics following irradiation. Gene expression analyses further demonstrated
that IEX-1 is enriched in intestinal mucosa and inducible following stimulation of
LPAR signaling.
Together, these findings demonstrate that survival signaling pathways play an
important role in determining tissue responses to radiation exposure. The results identify
LPAR signaling as a promising therapeutic target for mitigation of gastrointestinal
radiation injury and establish IEX-1 as a regulator of tissue radiosensitivity, providing a
basis for further investigation into mechanisms governing radiation response and the
development of improved radiation countermeasures.
