Improving Gastrointestinal Recovery after Radiation

描述（由申请方提供）：胃肠道（GI）对辐射损伤高度敏感。辐射暴露后胃肠道的实质性损伤导致死亡。迫切需要制定具体的对策，防止肠道受到辐射而造成的致命性。该项目的目的是研究三种有前途的药物，这些药物可能会显着改善致死剂量照射后的胃肠道恢复，使用完善的狗模型。这些药物是：角质形成细胞生长因子（KGF）、碳酸锂（Li2CO3）和二丙酸倍氯米松（BDP）的GI特异性制剂，其在暴露于以高剂量率施用的致死剂量的全身照射（TBI）后单独或组合施用。KGF刺激肠上皮细胞增殖并对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 β），通过wnt/连环蛋白信号通路激活肠干细胞增殖。我们认为肠道局部BDP可以减少放射损伤胃肠道引起的炎症细胞因子风暴。用于GI和造血损伤的辐射暴露犬模型是稳健的，并且该模型具有将临床前发现转化为临床环境的良好记录。在目标1中，将在TBI后给予减轻GI辐射综合征的药物，在目标2中，将在TBI前后给予药物，以实现具有良好GI道恢复的犬的存活。基于我们在该模型中的先前工作，我们将开始以0.7戈伊/min的剂量率以10戈伊的TBI剂量治疗犬，并且我们将用自体骨髓加标准支持性护理治疗犬，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天的生存率和GI放射综合征的恢复。在该模型中，GI辐射防护药物定义为与单独的标准支持治疗相比，实现显著改善的生存率（≥ 70%）。在随后的实验中，TBI剂量将以2戈伊的增量连续增加，并且将用单一药物或组合辐射防护药物治疗狗。在目标3中，基于AI-066498项目Bioshield "细胞因子用于急性辐射免疫保护"中的并行研究结果，我们将研究接受TBI但无自体骨髓支持的犬，给予（a）GI放射防护治疗的最佳组合和（B）从辐射造血综合征中恢复的最佳细胞因子治疗。“研究完成后，我们将确定GI综合征的最佳药物治疗和最高剂量的TBI，无论有没有造血干细胞支持，都可以可靠地存活。

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.