Improving Gastrointestinal Recovery after Radiation

改善放射后胃肠道恢复

• 批准号: 7472932
• 负责人: GEORGE Earl GEORGES
• 金额: $ 100万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472932
• 关键词: Acute; Antibiotics; Apoptotic; Autologous; Beclomethasone Dipropionate; Bioshield; Blood Transfusion; Bone Marrow; Canis familiaris; Cell Proliferation; Cessation of life; Clinical; Cohort Studies; Dose; Dose-Rate; Drug Formulations; End Point; Epithelial Cells; Exposure to; Gastrointestinal tract structure; Hematopoietic; Hematopoietic stem cells; IV Fluid; Immune; Inflammatory; Injury; Intestines; Lithium; Lithium Carbonate; Localized; Modeling; Pharmaceutical Preparations; Radiation; Radiation Syndromes; Radiation induced damage; Radiation-Protective Agents; Radioprotection; Recovery; Signal Pathway; Standards of Weights and Measures; Stem cells; Supportive care; Syndrome; Translating; Whole-Body Irradiation; Work; base; cytokine; day; gastrointestinal; glycogen synthase kinase 3 beta; improved; intestinal epithelium; irradiation; keratinocyte growth factor; pre-clinical; radiation recovery; research study

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.

描述（由申请人提供）：胃肠道（GI）对辐射损伤高度敏感。辐射暴露后胃肠道的严重损伤会导致死亡。迫切需要制定针对肠道暴露于辐射造成的死亡的具体对策。该项目的目的是研究三种有前途的药物，这些药物可能会使用完善的狗模型显着改善致命剂量照射后胃肠道的恢复。这些药物包括：角质细胞生长因子 (KGF)、碳酸锂 (Li2CO3) 和胃肠道专用制剂二丙酸倍氯米松 (BDP)，在暴露于致死剂量的高剂量率全身照射 (TBI) 后，可单独或联合用药。 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酶激酶 3 beta (GSK-3¿)，后者通过 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 可以减少由辐射损伤的胃肠道引起的炎症细胞因子风暴。胃肠道和造血损伤的辐射暴露狗模型是稳健的，并且该模型在将临床前发现转化为临床环境方面拥有良好的记录。在目标 1 中，将在 TBI 后给予缓解胃肠道辐射综合征的药物，在目标 2 中，将在 TBI 前后给予药物，以实现胃肠道恢复良好的狗的生存。根据我们之前在该模型中的工作，我们将从 10 Gy 的 TBI 剂量（0.7 Gy/min 的剂量率）开始，我们将使用自体骨髓以及标准支持护理（包括广谱抗生素、输血支持和静脉输液）来治疗狗。这使我们能够专注于治疗胃肠道辐射综合征，而不是治疗造血综合征的并发症。研究终点是第 30 天的存活率和胃肠道辐射综合症的恢复。在此模型中，胃肠道辐射防护药物被定义为与单独使用标准支持治疗相比，可显着提高生存率 (= 70%)。在后续实验中，TBI剂量将依次增加2 Gy增量，并对犬进行单药或联合防辐射药物治疗。在目标 3 中，我们将研究在没有自体骨髓支持的情况下接受 TBI 的狗，同时考虑 (a) 胃肠道辐射防护治疗的最佳组合和 (b) 用于从辐射造血综合征中恢复的最佳细胞因子治疗，基于 AI-066498 Bioshield 项目“用于急性辐射免疫保护的细胞因子”中同时研究的结果。研究完成后，我们将确定治疗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都能可靠存活的 TBI 最高剂量。