GENETIC BASIS OF RADIATION INDUCED FIBROSIS

描述：(改编自调查人员的摘要)这一目标 该项目是为了更好地了解糖尿病的遗传基础 辐射诱导的正常组织纤维化，从而使合理 这一晚期辐射后遗症的预测分析方法的发展 心理治疗。这些研究的理论基础是基于对人类的观察。 对实验动物的研究表明，对 辐射诱导的组织纤维化是受基因调控的，尽管没有 涉及个体变异的基因已经被识别出来。 尽管如此，正在开发的分析方法是为了前瞻性地识别 在治疗开始前，在诊所中的易感人群。这个 拟议的工作将集中于确定遗产的继承模式 放射性肺纤维化在两个杂交后代中的F2代 小鼠品系表现出明显不同的易感性 辐射诱导的纤维化，并随后绘制出 解释这些差异的原因。方法将是使用C57B1/6 小鼠，一种高度纤维化的品系，以及C3H/HeJ小鼠，一种弱的 并对这些小鼠进行饲养，获得F1和F2后代。至 确定辐射后纤维化的遗传模式，F2s将 暴露在单一剂量的辐射下，会导致显著的差异 在肺纤维化中的亲本菌株。照射后肺纤维化 将在整个肺中被定量，通过确定一个 肺组织切片显示特征性纤维化 表型。纤维化将使用计算机图像分析进行量化 安装在显微镜上的系统。用于基因定位，432辐射后的DNA F2小鼠将被用于识别150个短序列重复(SSR)，这些短序列重复是 C57B1/6和C3H/HeJ小鼠之间存在多态。肝组织纤维化的程度 F2代将与其SSR基因型相关。的继承模式 博莱霉素性肺纤维化的特点是。博莱霉素 将要进行的研究将构成绘制控制基因座的地图 博莱霉素诱导432只F2小鼠肺纤维化的研究从以下来源获得的数据 这些研究对临床放射治疗具有潜在的重要性，因为它们 应为发展预测分析提供合理的基础。 正常组织中的纤维化，这将使放射治疗师能够 前瞻性地识别敏感和耐药的个体，从而 避免过量服用对辐射敏感的个体，同时不损害 剂量给“正常”的人。最终结果将是更多的治疗方法。

DESCRIPTION: (adapted from the investigator's abstract) The goal of this project is to provide a better understanding of the genetic basis of radiation-induced fibrosis in normal tissues so as to enable the rational development of predictive assays for this late sequelae of radiation therapy. The rationale for these studies is based on observations in humans and studies in experimental animals which suggest that sensitivity to radiation-induced tissue fibrosis is genetically regulated, although none of the genes involved in individual variation have been identified. Nonetheless, assays are being developed to prospectively identify susceptible individuals in the clinic before treatment commences. The proposed work will focus on determining the pattern of inheritance of radiation-induced lung fibrosis in the F2 progeny of an intercross of two mouse strains shown to differ markedly in their susceptibility to radiation-induced fibrosis, and subsequently mapping the locus (loci) that account for these differences. The approach will be to use the C57B1/6 mouse, a highly fibrogenic strain, and the C3H/HeJ mouse, a weakly fibrogenic strain and to breed these mice to obtain F1 and F2 progeny. To determine the inheritance pattern of fibrosis after irradiation, F2s will be exposed to a single dose of radiation which induces a significant difference in lung fibrosis in the parental strains. Lung fibrosis after irradiation will be quantitated in the whole lung by determining the area of a histological section of lung displaying the characteristic fibrotic phenotype. Fibrosis will be quantitated using a computerized image analysis system attached to a microscope. For gene mapping, DNA from 432 irradiated F2 mice will be used to type for 150 short sequence repeats (SSR) that are polymorphic between C57B1/6 and C3H/HeJ mice. The extent of fibrosis in the F2s will be correlated with their SSR genotype. The inheritance pattern of bleomycin-induced lung fibrosis had been characterized. The bleomycin studies to be performed will constitute mapping the loci that control bleomycin-induced lung fibrosis in 432 F2 mice. The data obtained from these studies have potential importance to clinical radiotherapy as they should provide a rational basis for the development of predictive assays for fibrosis in normal tissue, that will enable the radiotherapist to prospectively identify both sensitive and resistant individuals, and thus avoid overdosing radiosensitive individuals while not compromising on the dose to "normal" individuals. The ultimate outcome would be more cures.