PGE2 mitigation of acute and late radiation injury

描述（由申请人提供）：本提案的总体目标是开发一种新的治疗方法-前列腺素E2 (PGE2) -以减轻放射对造血系统的影响。这种强健的细胞系统受到辐射的破坏和破坏，导致细胞减少，导致危及生命的感染、贫血和出血。血小板损失的发生和程度预测全身照射后的生存。已经开发和储存的用于放射紧急情况的大多数药剂都是专门针对白细胞损失的临床后果的。尽管在过去的几十年里已经做了很多工作，但很少有药物从实验室过渡到临床。罗彻斯特大学辐射医疗对策中心的Palis和Calvi实验室的合作研究已开发出强大的急性和晚期辐射损伤小鼠模型。我们的初步研究表明，急性辐射暴露后48-72小时给予PGE2，可减轻巨核细胞谱系，导致血小板更快恢复。此外，PGE2可显著减少表型HSC的数量。我们假设PGE2通过骨髓微环境，特别是内皮细胞和巨噬细胞群体水平起作用，以减轻辐射诱导的造血干细胞和巨核细胞前体损伤。我们将评估PGE2缓解急性和晚期血液学损伤的有效性和机制。我们的联合研究还确定了一种特殊的群体——14天大的小鼠——对相对较低的亚致死辐射暴露特别敏感，因为它们不仅会出现表型hsc的严重减少，还会出现晚期外周细胞减少。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提议的药物的不同反应。因此，我们还将研究PGE2在儿童和成人人群中减轻晚期造血系统损伤的功效。综上所述，我们提出的合作机制研究将提出PGE2，这是一种有前景的新型药物，具有既定的安全性，可用于减轻辐射暴露的急性和晚期效应。

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.