Screening to identify protectors and mitigators of Radiation GI Syndrome

辐射恐怖袭击、意外辐射暴露或辐射事故的可能性导致迫切需要确定具有辐射防护能力或缓解潜在致命全身或部分辐射暴露的制剂。有三种典型的急性放射综合征：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。GI综合征通常发生在人类6-10Gy值的剂量范围内(阈值)，并在两周内致命。在GI综合征中，胃肠道受到不可修复的损害，出现大量的肠细胞坏死和凋亡。肠上皮剥脱导致脱水和电解质失衡，导致分泌性腹泻。此外，细菌通过受损的肠粘膜屏障迁移，再加上骨髓抑制，导致感染和脓毒症的高风险。骨髓和肠道中分化细胞和干细胞的死亡与GI综合征的发病机制有关。需要确定能够保护肠道细胞和骨髓免受辐射伤害的制剂(保护剂)和能够减轻潜在致命性暴露影响的制剂(缓释剂)。为了在潜在致命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，任何已确定的药剂都应该在两个组织间隔(肠道和骨髓)都有效。传统的化合物筛选有效预防GI综合征的药物需要对计算LD50/10的动物模型进行大量投资(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。以一种概括体内情况的方式在体外筛选化合物的能力将极大地促进体内研究试剂的鉴定。我们的实验室最近开发了体外方法，允许以一种方式对肠道有机物质进行测试，这种方法可以概括使用已知辐射防护剂和减震剂获得的体内结果(在辐射研究会2015年上公布)。该项目将利用这一专业知识来确定要研究的候选特工。

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 to identify candidate agents for study.