KIDNEY RESPONSE TO RADIATION AND CHEMOTHERAPY

描述：本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。 所涉提议主要是 发现放射性肾病是放射性肾病的主要并发症， 全身照射用于骨髓移植（BMT）， 大鼠是这种肾病的极好模型， 血管紧张素转换酶（ACE）抑制剂和血管紧张素II（AII） 阻断剂可用于治疗BMT肾病。 这些研究强烈地 受ACE抑制剂和AII阻滞剂可以 永久干扰BMT肾病的发展，即使 在照射后开始治疗，并且不能无限期地继续。 这些发现对晚期癌症的标准机械解释提出了质疑。 辐射损伤，并打开了正常组织辐射的可能性， 损伤可以通过后照射来治疗甚至预防， 干预措施。 本提案的具体目的是：1）测试 放射诱导激活肾素-血管紧张素系统假说 (RAS)是辐射（和骨髓移植）肾病的原因。 2)测试 假设纤维化是一个原因，而不是一个结果， 放射性肾病 3)为了验证AT 1受体 拮抗剂优选有效预防和治疗 放射性（和BMT）肾病。 4)回顾性地评估这些因素 影响人类BMT肾病的发病率。 5)为确定装甲运 一项前瞻性随机临床试验， 降低BMT肾病的发生率。 6)为确定 肾耐受性对照射时年龄的依赖性，以及这种变化是否 耐受性的降低与ACE抑制剂在 年长的动物 7)为了确定脉冲低剂量 低剂量率（LDR）和连续LDR产生临床等效的正常组织 损伤

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.