GENETIC BASIS OF RADIATION INDUCED FIBROSIS

辐射诱发纤维化的遗传基础

• 批准号: 2414329
• 负责人: ELIZABETH L TRAVIS
• 金额: $ 18.7万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-15 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414329
• 关键词: bleomycin; breath tests; computer program /software; genetic mapping; genotype; imaging /visualization /scanning; laboratory mouse; neoplasm /cancer genetics; phenotype; pulmonary fibrosis /granuloma; radiation genetics; radiation related neoplasm /cancer

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.

描述：（改编自研究者摘要） 项目是为了更好地了解遗传基础， 辐射诱导的正常组织纤维化，以便能够合理地 发展这种辐射晚期后遗症的预测分析 疗法 这些研究的理由是基于对人类的观察 对实验动物的研究表明， 辐射诱导的组织纤维化是遗传调节的，尽管没有一个 参与个体变异的基因已经被鉴定出来。 尽管如此，正在开发检测方法，以前瞻性地识别 在治疗开始之前，在诊所对易感个体进行检查。 的 拟议的工作将集中在确定遗传模式， 在两个杂交的F2后代中辐射诱导的肺纤维化 小鼠品系显示出在它们对 辐射诱导的纤维化，并随后映射位点（位点）， 解释这些差异。 该方法将使用C57B1/6 小鼠，一种高度纤维化的品系，和C3H/HeJ小鼠，一种弱纤维化的品系。 并将这些小鼠繁殖以获得F1和F2后代。 到 确定照射后纤维化的遗传模式，F2s将是 暴露于单一剂量的辐射， 肺纤维化的发生率。 照射后肺纤维化 将通过测定肺的面积在整个肺中定量。 肺组织切片显示特征性纤维化 表型 将使用计算机图像分析对纤维化进行定量 系统连接到显微镜。 为了进行基因绘图， F2小鼠将用于对150个短序列重复（SSR）进行分型， C57B1/6和C3H/HeJ小鼠之间的多态性。 纤维化的程度 F2代的遗传多样性与其SSR基因型相关。 的遗传模式 博来霉素诱导的肺纤维化已经被表征。 博来霉素 将要进行的研究将包括绘制控制 博来霉素诱导的432 F2小鼠肺纤维化。 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 应提供一个合理的基础，为发展预测分析， 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个体，从而 避免对辐射敏感的人过量用药，同时不影响 对“正常人”的影响。 最终的结果将是更多的治愈。