Improving Gastrointestinal Recovery after Radiation

描述（申请人提供）：胃肠道对辐射损伤高度敏感。辐射暴露后对胃肠道的严重伤害会导致死亡。迫切需要制定具体的对策，以防止肠道暴露于辐射造成的致死率。本项目的目的是研究三种有希望的药物，这些药物可能会显著改善致死剂量照射后胃肠道的恢复，并使用成熟的狗模型。这些药物是：角化细胞生长因子（KGF）、碳酸锂（Li2CO3）和gi特异性制剂二丙酸倍氯米松（BDP），在暴露于致死剂量的高剂量全身照射（TBI）后单独或联合使用。KGF刺激肠上皮细胞增殖，对肠上皮细胞具有抗凋亡活性。锂特异性抑制糖原合成酶激酶3 β (GSK-3)， GSK-3通过wnt / catenin信号通路激活肠道干细胞增殖。我们认为肠道定位的BDP可以减少辐射损伤胃肠道引起的炎症细胞因子风暴。狗的GI和造血损伤辐射暴露模型是稳健的，并且该模型具有将临床前研究结果转化为临床环境的良好记录。在Aim 1中，减轻胃肠道辐射综合征的药物将在TBI后给予，在Aim 2中，药物将在TBI前后给予，以实现犬的生存和良好的胃肠道恢复。基于我们之前在该模型中的工作，我们将以10gy的TBI剂量以0.7 Gy/min的剂量率开始，我们将用自体骨髓加上标准的支持治疗，包括广谱抗生素、输血支持和静脉输液。这使我们能够专注于治疗胃肠道放射综合征，而不是治疗造血综合征的并发症。研究终点是第30天的生存和胃肠道放射综合征的恢复。在这个模型中，GI放射保护药物被定义为与单独的标准支持治疗相比，显著提高生存率（= 70%）。在后续的实验中，TBI剂量将以2gy的增量依次增加，狗将接受单药或联合放射防护药物治疗。在Aim 3中，我们将根据AI-066498项目Bioshield“细胞因子对急性辐射的免疫保护”的并行研究结果，研究在没有自体骨髓支持的情况下接受TBI的狗，同时给予(a) GI放射保护治疗的最佳组合和(b)放射造血综合征恢复的最佳细胞因子治疗。研究完成后，我们将确定胃肠道综合征的最佳药物治疗方法，以及在有或没有造血干细胞支持的情况下可靠存活的TBI的最高剂量。

DESCRIPTION (provided by applicant): The gastrointestinal (GI) tract is highly sensitive to radiation damage. Substantial injury to the GI tract after radiation exposure results in death. There is an urgent need to develop specific countermeasures against the lethality caused by intestinal exposure to radiation. The aim of this project is to study three promising drugs that are likely to significantly improve GI recovery after lethal dose irradiation using the well-established dog model. The drugs are: keratinocyte growth factor (KGF), lithium carbonate (Li2CO3), and a GI-specific formulation of beclomethasone dipropionate (BDP) to be given alone or in combination after exposure to lethal doses of total body irradiation (TBI) administered at a high dose rate. KGF stimulates intestinal epithelium cell proliferation and has anti-apoptotic activity on epithelial cells. Lithium specifically inhibits glycogen synthase kinase 3 beta (GSK-3¿) which activates intestinal stem cell proliferation via the wnt / ¿ catenin signaling pathway. We propose that gut-localized BDP can reduce the inflammatory cytokine storm induced by the radiation damaged GI tract. The dog model of radiation exposure for GI and hematopoietic injury is robust, and the model has a strong track record of translating preclinical findings to the clinical setting. In Aim 1, the drugs to mitigate the GI radiation syndrome will be given after TBI, and in Aim 2, the drugs will be given before and after TBI to achieve survival of dogs with good GI tract recovery. Based on our prior work in this model, we will begin with a TBI dose of 10 Gy at 0.7 Gy/min dose rate, and we will treat dogs with autologous bone marrow plus standard supportive care including broad spectrum antibiotics, blood transfusion support, and intravenous fluids. This permits us to focus on treating the GI radiation syndrome, rather than on treating complications of the hematopoietic syndrome. The study end point is survival at day 30 and recovery from GI radiation syndrome. In this model, a GI radioprotective drug is defined as achieving significantly improved survival (= 70%) compared to standard supportive care alone. In the subsequent experiments, the TBI dose will be successively increased by 2 Gy increments, and dogs will be treated with single-drug or combined radioprotective drugs. In Aim 3 we will study dogs given TBI without autologous bone marrow support given both (a) the optimal combination of GI radioprotection treatment and (b) optimal cytokine treatment for recovery from the radiation hematopoietic syndrome, based on the results of concurrent studies in AI-066498 Project Bioshield "Cytokines for immune protection from acute radiation." Upon study completion, we will have identified the optimal drug treatment for the GI syndrome and the highest dose of TBI that can be reliably survived both with and without hematopoietic stem cell support.