KIDNEY RESPONSE TO RADIATION AND CHEMOTHERAPY

描述：该项目的目标是使用啮齿动物模型来研究 晚期放射性组织损伤的机制。该提案的基础是 发现放射性肾病是慢性肾炎的主要并发症 全身照射用于骨髓移植(BMT)， 大鼠是这种肾病的一个很好的模型，而且发现 血管紧张素转换酶(ACE)抑制剂与血管紧张素II(AII) 阻滞剂可用于治疗骨髓移植肾病。这些研究具有很强的针对性 受ACE抑制剂和AII受体阻滞剂的研究结果影响 永久性干预骨髓移植肾病的发展，即使在 治疗在照射后开始，不会无限期地继续下去。 这些发现使人们对迟发的标准机制解释产生了怀疑。 辐射损伤，并开启了正常组织辐射的可能性 损伤可以通过放射后治疗，甚至预防。 干预措施。这项建议的具体目的是：1)测试 假设辐射诱导肾素-血管紧张素系统的激活 (RAS)是放射性(和骨髓移植)肾病的原因。2)测试 假设纤维化是导致而不是结果 放射性肾病。3)检验AT1受体的假设 拮抗剂在预防和治疗高血压病中优先有效。 放射性(和骨髓移植)肾病。4)对影响因素进行回顾评估 对人类骨髓移植肾病发病率的影响。5)确定 卡托普利能否用于临床的前瞻性随机试验 降低骨髓移植肾病的发生率。6)确定 肾脏耐受性与照射年龄的相关性，以及这种变化 在耐受性方面与血管紧张素转换酶抑制剂的有效性降低有关 年长的动物。7)确定脉冲低剂量的条件 率(LDR)和连续LDR产生临床上相同的正常组织 受伤。

DESCRIPTION: The goal of this project is to use rodent models to study the mechanism of late radiation-induced tissue injury. The proposal is based on the discovery that radiation nephropathy is a major complication of the total body irradiation used in bone marrow transplantation (BMT), that the rat is an excellent model for this nephropathy, and the discovery that angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AII) blockers could be used to treat BMT nephropathy. The studies are strongly influenced by the finding that ACE inhibitors and AII blockers can permanently interfere with the development of BMT nephropathy even when treatment is started after irradiation and is not continued indefinitely. These findings cast doubt on the standard mechanistic explanations for late radiation injury, and open up the possibility that normal tissue radiation injuries can be treated, or even prevented, by post-irradiation interventions. The specific aims of this proposal are: 1) To test the hypothesis that radiation-induced activation of the renin-angiotensin system (RAS) is the cause of radiation (and BMT) nephropathy. 2) To test the hypothesis that fibrosis is a cause , rather than a consequence , of radiation nephropathy. 3) To test the hypothesis that AT1 receptor antagonists are preferentially effective in the prophylaxis and treatment of radiation (and BMT) nephropathy. 4) To retrospectively assess the factors influencing the incidence of BMT nephropathy in humans. 5) To determine in a prospective randomized clinical trial whether captopril can be used to lower the incidence of BMT nephropathy. 6) To determine the basis for the dependence of renal tolerance on age-at-irradiation, and whether the change in tolerance is related to the decreased effectiveness of ACE inhibitors in older animals. 7) To determine the conditions under which pulsed low dose rate (LDR) and continuous LDR produce clinically equivalent normal tissue injury.