Friday, May 9, 2025
5/9/2025
Ghrelin as Radiation Countermeasure: Mechanism of Its Action - PROJECT DESCRIPTION: This U01 project aims to elucidate a novel neuroenteric mechanism through which ghrelin confers intestinal radioprotection, and to preclinically develop human ghrelin as a safe and effective mitigator for gastrointestinal acute radiation syndrome (GI-ARS). Ghrelin is a small peptide secreted by the stomach that readily crosses the blood-brain barrier. In our preliminary studies, ghrelin significantly improved the intestinal integrity and survival in the context of inflammatory enteropathy. After radiation injury, serum levels of ghrelin were markedly decreased, and ghrelin treatment significantly improved intestinal integrity, increased crypt depth, and doubled the survival rate. Interestingly, ghrelin’s protective effects in radiation combined injury were abrogated by prior subdiaphragmatic vagotomy, indicating that ghrelin primarily acts in the central nervous system with its beneficial effects conveyed to the gut through the vagus nerve. Next, we established ghrelin’s dose-response to improve survival after partial body irradiation, a better model to study severe GI-ARS. After radiation exposure, dying intestinal stem cells (Lgr5+ cells) must be replenished by otherwise quiescent clusterin (Clu+) revival stem cells. We demonstrated the feasibility of evaluating Lgr5+ stem cells as the target on ghrelin’s neuroenteric regulation, and showed that both Lgr5+ stem cells and Clu+ revival stem cells express cholinergic receptors. As such, we hypothesize that ghrelin mitigates radiation injury via the efferent vagus nerve and the enteric nervous system to promote intestinal crypt Lgr5+ stem cell recovery from Clu+ revival stem cells. Human ghrelin has been evaluated in Phase I clinical trials with an excellent safety profile. Moreover, it can be synthesized in large quantities for mass emergency needs. Based on our positive preliminary results, we also hypothesize that human ghrelin can be further developed as an effective GI-ARS mitigator. In this proposal, we will elucidate ghrelin’s neuroenteric mechanism, its effects on Lgr5+ stem cells and Clu+ revival stem cells, and its efficacy, PK, and safety pharmacology as a mitigator for GI-ARS. These studies shall characterize human ghrelin’s novel mechanism of action and develop it as a safe and effective countermeasure for victims of major radiation exposure.
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