KIDNEY RESPONSE TO RADIATION AND CHEMOTHERAPY

这个项目的长期目标是利用啮齿动物的肾脏耐受性 研究缓慢更新组织对辐射的迟发反应的模型， 以及抗肿瘤药物治疗对这一晚期反应的影响。 发现放射性肾病是一种主要并发症 与用于人骨的全身照射(TBI)有关 骨髓移植(BMT)条件作用增加了一个重要的临床前阶段 此项目的组成部分。该项目现在有两个互补的重点， 用大鼠放射性肾炎模型作为治疗放射性肾炎的通用模型 研究放射治疗对晚期正常组织的影响；以及使用 大鼠骨髓移植模型研究骨髓移植的病因、治疗和预防 肾病。 迟发性反应正常组织的放射生物学研究进展 都受到了肾辐射损伤修复的发现的影响 在低剂量后，每组分的剂量都不符合线性二次 (α/β)模型，也不是简单的单指数修复模型。这个 研究旨在： 证实大鼠放射性损伤修复的动力学 肾脏不遵循简单的单指数修复动力学，并且 确定修复动力学依赖于 损害程度。 确定肾脏耐受性是否偏离线性- 二次(α/β)模型是统计和/或生物学上的 意义重大。 确定肾脏耐受性与剂量率的关系；评估 它如何与标准模型的预测相结合；并确定如何 低剂量率和高剂量率照射存在交互作用。 骨髓移植肾病的拟议研究在很大程度上是基于最近的 放射性肾炎与骨髓移植肾病发生发展的关系 可通过卡托普利治疗延缓或可能预防 血管紧张素转换酶(ACE抑制剂。这些研究是设计的 致： 确定ACE抑制剂、钙通道阻滞剂和其他 抗高血压药物在防治骨髓移植中的应用 肾病。 确定卡托普利延缓血管紧张性心脏病发生的机制 放射性肾炎。 确定内皮细胞衍生的松弛因子缺乏在 实验性骨髓移植肾病。 完成正在进行的肾毒性药物是否用于 与BMT相结合，促进或加速辐射发展 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.