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型疗法-前列腺素E2（PGE 2）-以减轻辐射对造血系统的影响。这种强大的细胞系统因暴露于辐射而被破坏和损坏，导致血细胞减少，从而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存活率。已开发和储存的用于放射性紧急情况的大部分药剂专门针对白色血细胞丢失的临床后果。虽然在过去的几十年里已经做了很多工作，但很少有代理商从板凳过渡到诊所。罗切斯特大学辐射医学对策中心的Palis和Calvi实验室的合作研究已经导致了急性和晚期辐射损伤的强大小鼠模型的开发。我们的初步研究表明，在急性辐射暴露后48-72小时递送的PGE 2减轻了巨核细胞谱系，导致更快的血小板恢复。此外，PGE 2急剧减少表型HSC的数量。我们假设PGE 2通过骨髓微环境，特别是在内皮细胞和巨噬细胞群体的水平上起作用，以减轻造血干细胞和巨核细胞前体的辐射诱导的损伤。我们将评估PGE 2缓解急性和晚期血液系统损伤的有效性和机制。我们的联合研究还确定了一个特殊的群体- 14日龄小鼠-作为相对lw亚致死辐射暴露特别敏感，因为他们不仅发展严重减少表型HSC，但也晚外周血细胞减少。更好地了解儿童和成人人群之间的差异反应，无论是辐射损伤和任何拟议的代理商，将需要开发具有广泛适用性的治疗。因此，我们还将研究PGE 2减轻儿童与成人人群造血系统晚期损伤的疗效。总之，我们提出的合作机制研究将提出PGE 2，一种具有既定安全性的有前途的新药物，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.