PGE2 mitigation of acute and late radiation injury

描述(由申请人提供)：这项建议的总体目标是开发一种新的疗法-前列腺素E2(PGE2)-以减轻辐射对造血系统的影响。这种强大的细胞系统会受到辐射的破坏和破坏，辐射会导致细胞减少，从而导致危及生命的感染、贫血和出血。血小板丢失的开始和程度预示着全身照射后的存活率。作为辐射紧急情况的一部分，已开发和储存的大多数制剂都专门针对白细胞丧失的临床后果。尽管在过去的几十年里已经做了很多工作，但很少有代理人从替补席过渡到临床。罗切斯特大学辐射医学对策中心内的Palis和Calvi实验室的合作研究导致了急性和晚期辐射损伤的健壮小鼠模型的发展。我们的初步研究表明，在急性辐射暴露后48-72小时交付的PGE2可以缓解巨核细胞谱系，导致更快的血小板恢复。此外，PGE2显著减少了表型HSC的数量。我们假设PGE2通过骨髓微环境发挥作用，特别是在内皮细胞和巨噬细胞群体的水平，以减轻辐射诱导的造血干细胞和巨核细胞前体细胞的损伤。我们将评估PGE2缓解急性和晚期血液系统损伤的有效性和机制。我们的联合研究还发现，一种特殊的群体--14日龄小鼠--对相对较低的亚致死剂量辐射特别敏感，因为它们不仅会出现表型HSC的严重减少，而且还会出现晚期外周血细胞减少症。为了开发具有广泛适用性的治疗方法，需要更好地了解儿童和成人人群对辐射损伤和任何拟议药物的不同反应。因此，我们还将研究PGE2对减轻儿童和成人人群造血系统晚期损伤的疗效。综上所述，我们提出的协作性、机械性研究将提出PGE2，这是一种有希望的新制剂，具有既定的安全性，用于减轻辐射暴露的急性和晚期影响。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop a novel therapy - prostaglandin E2 (PGE2) - to mitigate the effects of radiation on the hematopoietic system. This robust cellular system is disrupted and damaged by exposure to radiation, which results in cytopenias leading to life-threatening infections, anemia, and bleeding. The onset and extent of platelet loss predicts survival following total body irradiation. The majority of agents that have been developed and stockpiled for use as part of a radiological emergency are specifically targeted at the clinical consequences of white blood cell loss. Although much work has been done over the past decades, few agents have transitioned from bench to clinic. The collaborative studies of the Palis and Calvi labs within the University of Rochester's Center for Medical Countermeasures against Radiation have resulted in the development of robust mouse models of acute and late radiation injury. Our preliminary studies indicate that PGE2, delivered 48-72 hours after acute radiation exposure, mitigates the megakaryocyte lineage leading to more rapid platelet recovery. In addition, PGE2 acutely mitigates the number of phenotypic HSC. We hypothesize that PGE2 acts through the marrow microenvironment, specifically at the level of endothelial cells and macrophage populations, to mitigate radiation-induced injury of hematopoietic stem cells and megakaryocyte precursors. We will assess the effectiveness and mechanism of PGE2 mitigation of acute and late hematologic injury. Our joint studies have also identified a special population - 14 day old mice - as being particularly sensitive to relatively lw sublethal radiation exposure, since they develop not only a severe reduction in phenotypic HSCs but also late peripheral cytopenias. A better understanding of the differential response between pediatric and adult populations, both to radiation injury and any proposed agents, will be required to develop treatments with broad applicability. We will, therefore, also investigate the efficacy of PGE2 to mitigate late injury to the hematopoietic system of pediatric versus adult populations. Taken together, our proposed collaborative, mechanistic studies will bring forward PGE2, a promising new agent with an established safety profile, for use in mitigating both acute and late effects of radiation exposure.