Screening to identify protectors and mitigators of Radiation GI Syndrome

放射性恐怖袭击、意外辐射照射或辐射事故的可能性导致迫切需要确定具有辐射防护或减轻可能致命的全身或部分辐射照射能力的物质。存在三种典型的急性辐射综合征：骨髓（造血）综合征、胃肠道（GI）综合征和心血管或中枢神经系统综合征。胃肠道综合征一般发生在人体6-10Gy（阈值）剂量范围内，两周内致死。在胃肠道综合征中，胃肠道受到不可修复的损伤，肠细胞大量坏死和凋亡。肠上皮的剥落通过分泌性腹泻导致脱水和电解质失衡。此外，细菌通过受损的肠粘膜屏障迁移，并结合骨髓抑制，导致感染和败血症的高风险。骨髓和肠道中分化细胞和干细胞的死亡与胃肠道综合征的发病机制有关。需要确定能够保护肠细胞和骨髓免受辐射损伤的制剂（保护剂）和能够减轻潜在致命照射影响的制剂（缓解剂）。为了在可能致死性全身暴露导致胃肠道综合征的情况下表现出最大的疗效，任何确定的药物都应该在两个组织区室（肠道和骨髓）都有效。对有效预防胃肠道综合征的药物进行传统的化合物筛选，需要在动物模型上进行大量投资，计算LD50/10（多剂量辐射，多剂量候选试剂，与辐射相关的多次暴露）。这些研究既昂贵又耗时。以概括体内条件的方式在体外筛选化合物的能力将大大促进体内研究的药物鉴定。我们的实验室最近开发了一种体外方法，可以以一种概括使用已知辐射保护剂和缓解剂获得的体内结果的方式测试肠道类器官（在辐射研究学会2015年发表）。该项目将利用该专业知识以及我们在致命性研究和基于骨髓的研究方面的专业知识来确定研究的候选药物。

The possibility of a radiologic terrorist attack, accidental radiation exposures, or radiation accident has led to a critical need to identify agents with the capacity of radioprotection or mitigation of potentially lethal total or partial body radiation exposures. Three classic acute radiation syndromes exist: bone marrow (hematopoietic) syndrome, gastrointestinal (GI) syndrome, and cardiovascular or CNS syndrome. GI syndrome generally occurs in the dose range of 6-10Gy in humans (threshold) and is lethal within two weeks. In GI syndrome, the GI tract is irreparably damaged with massive necrosis and apoptosis of enterocytes. Denudation of the intestinal epithelia leads to dehydration and electrolyte imbalance via a secretory diarrhea. Additionally, the transmigration of bacteria through the damaged intestinal mucosal barrier in combination with bone marrow suppression results in a high risk of infection and sepsis. Death of both differentiated cells and stem cells in the marrow and gut are implicated in the pathogenesis of GI syndrome. Identification of agents that can protect intestinal cells and bone marrow from radiation injury (protectors) and agents that can mitigate the effects of potentially lethal exposures (mitigators) are needed. In order to exhibit maximal efficacy for the context of potentially lethal total body exposures that results in GI syndrome, any identified agents should be effective in both tissue compartments (gut and marrow). Traditional compound screening for agents effective in preventing GI syndrome requires a substantial investment in animal models in which an LD50/10 is calculated (multiple doses of radiation, multiple doses of candidate reagent, multiple times of exposure in relation to radiation). These studies are costly and time consuming. The ability to screen compounds in vitro in a fashion that recapitulates the in vivo condition would significantly facilitate identification of agents for in vivo study. Our laboratory has recently developed in vitro methods that allow testing of intestinal organoids in a fashion that recapitulates in vivo results obtained with known radiation protectors and mitigators (presented at Radiation Research Society 2015). This project will leverage that expertise as well as our expertise in lethality studies and bone marrow based studies to identify candidate agents for study.