KIDNEY RESPONSE TO RADIATION AND CHEMOTHERAPY

本项目的长期果阿是使用一种啮齿类动物的肾耐受性 模型来研究缓慢更新组织对辐射的晚期反应， 以及抗肿瘤药物治疗对这种迟发反应的影响。 发现放射性肾病是一种主要的并发症 与用于人体骨的全身照射（TBI）相关 骨髓移植（BMT）预处理增加了一个主要的临床前 这个项目的组成部分。该项目现在有两个互补的重点， 使用大鼠放射性肾炎模型作为一般模型， 研究放射治疗对正常组织的后期影响;以及 大鼠骨髓移植模型，研究骨髓移植的病因、治疗和预防 肾病 迟发反应正常组织放射生物学的拟议研究 受到肾脏辐射损伤修复的发现的影响 低剂量后，每部分既不遵循线性二次方程， （α/β）模型，也不是简单的单指数修复模型。的 研究旨在： 证实大鼠辐射损伤修复的动力学 肾脏不遵循简单单指数修复动力学， 确定修复动力学依赖于 伤害程度。 确定肾耐受性是否偏离线性- 二次（α/β）模型在统计学和/或生物学上 显著 确定肾耐受性与剂量率之间的关系;评估 它如何与标准模型的预测;并确定如何 低剂量率和高剂量率辐照相互作用。 BMT肾病的拟议研究在很大程度上是基于最近的 发现放射性肾炎和骨髓移植肾病的发展 可以延缓，并可能预防，治疗与卡托普利， 血管紧张素转换酶（ACE抑制剂）。研究的目的是 收件人： 确定ACE抑制剂、钙通道阻滞剂和其他 抗高血压治疗方案在骨髓移植中的应用 肾病 确定巯甲丙脯酸延缓发展的机制， 放射性肾炎 确定内皮源性舒张因子缺乏在 实验性BMT肾病 完成正在进行的研究，以确定是否有肾毒性药物用于 与BMT结合增强或加速辐射的发展 肾炎

The long-term goa of this project is to use a rodent renal tolerance model to study the late response of slow renewal tissues to irradiation, and the impact of anti-neoplastic drug treatment on this late response. The discovery that radiation nephropathy is a major complication associated with the total body irradiation (TBI) used for human bone marrow transplant (BMT) conditioning has added a major preclinical component of this project. The project now has two complementary foci, the use of the rat radiation nephritis model as a general model for studying the late normal tissue effects of radiotherapy; and the use of the rat BMT model to study the cause, treatment and prevention of BMT nephropathy. Proposed studies of the radiobiology of late responding normal tissue are influenced by the discovery that repair of renal radiation damage after low doses per fraction follows neither the linear-quadratic (alpha/beta) model nor a simple mono-exponential repair model. The studies are designed to: Confirm that the kinetics of repair of radiation damage in the rat kidney do not follow simple mono-exponential repair kinetics, and determine the mechanism for the dependence of repair kinetics on the level of damage. Determine whether the deviance of renal tolerance from the linear- quadratic (alpha/beta) model is statistically and/or biologically significant. Determine the relationship between renal tolerance and dose-rate; assess how it comes with the predictions of standard models; and determine how low dose rate and high dose rate irradiation interact. Proposed studies of BMT nephropathy are heavily based on the recent findings that the development of radiation nephritis and BMT nephropathy can be retarded, and possibly prevented, by treatment with captopril, an angiotensin converting enzyme (ACE inhibitor. The studies are designed to: Determine the role ACE inhibitors, calcium-channel blockers, and other anti-hypertensive regimens in the prevention and treatment of BMT nephropathy. Determine the mechanism by which captopril retards the development of radiation nephritis. Determine the role of endothelium-derived relaxing factor deficiency in experimental BMT nephropathy. Complete the on-going study of whether nephrotoxic drugs used in conjunction with BMT enhance or accelerate the development of radiation nephritis.