Modeling Chromosome Aberrations

染色体畸变建模

• 批准号: 9971169
• 负责人: Rainer Sachs
• 金额: $ 43.26万
• 依托单位: University of California-Berkeley
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9971169&HistoricalAwards=false
• 关键词: Modeling; Chromosome; Aberrations

Sachs9971169 Ionizing radiation produces chromosome aberrations, throughbreakage and large-scale reshuffling of chromosomes. Usingfluorescent in situ hybridization techniques to paint variouschromosomes different colors reveals a rich variety of simple andcomplex aberrations, each putatively indicative of two or moreDNA double strand breaks involved in one over-all misrepairreaction. The investigator undertakes calculations on thebiophysical implications of current data on aberrations, and ofpulsed-field gel-electrophoresis data on DNA double strand breakclustering along chromosomes, relevant to the early stages ofaberration formation. Three basic molecular models for DNA breakmisrejoining are compared. There are so many combinatorialpossibilities for this misrejoining that theorems, equations, andcomputer simulations are needed for systematically interpretingthe extensive, elaborate current data. The main methods are: (1)suitably adapting standard results of probability theory andstochastic process theory, mainly on Poisson cluster pointprocesses; and (2), extending CAS (chromosome aberrationsimulator) computer software. Collaborations with many differentexperimental groups world-wide are continued. Models that assumerandomness of break induction and misrepair can characterize withreasonable accuracy, using only two adjustable parameters, therelative frequencies of many different types of aberrations andtheir dependence on genomic content of the chromosome armsinvolved. Understanding the effects of ionizing radiation on cells isan important part of fundamental biology. Chromosome aberrationsare complex cellular endpoints, copiously produced by ionizingradiation and informative about basic mechanisms of DNA damageproduction, repair, and misrepair. Aberrations are also robustlyimplicated in the main areas of applied radiobiology, includingcancer risk assessment, estimating cell killing duringradiotherapy, and biodosimetry (i.e. judging past exposure of anindividual to radiation, e.g. after a radiation accident or anastronaut's mission). Due to increased current interest and toimproved experimental techniques, there has been a flood of newdata on radiation-induced aberrations. The investigator studiesthe underlying biophysics of chromosome aberration formation,using state-of-the-art mathematical and computer methods. Hismethods discriminate between the three current molecular modelsof aberration formation, which are needed mainly to predictlevels of radiation damage in situations not yet measuredexperimentally, such as doses too low to be readily tractable inlaboratory analyses but nonetheless of possible concern for largepopulations. Mathematical and computer modeling is acomparatively inexpensive way to maximize biological informationobtainable from the rapidly increasing databases and to helpguide experiments.

Sachs9971169电离辐射会导致染色体畸变、穿透和染色体的大规模重新洗牌。用荧光原位杂交技术绘制各种不同颜色的染色体，发现了各种各样的简单和复杂的异常，每一种都可能表明在一个全面的错误修复反应中涉及两个或两个以上的DNA双链断裂。研究人员负责计算目前关于像差的数据和关于DNA双链断裂沿染色体聚集的脉冲场凝胶电泳数据的生物物理意义，这与细胞形成的早期阶段有关。比较了DNA断裂再连接的三种基本分子模型。对于这种重新连接，有如此多的组合可能性，以至于需要定理、方程和计算机模拟来系统地解释广泛而详细的当前数据。其主要方法是：(1)适当地采用概率论和随机过程理论的标准结果，主要针对Poisson聚集点过程；(2)扩展CAS(染色体畸变模拟器)计算机软件。与世界各地许多不同的实验小组的合作仍在继续。假设断裂诱导和错误修复是随机性的模型，只需两个可调参数，许多不同类型的畸变的相对频率及其对所涉及的染色体臂的基因组含量的依赖，就可以以合理的精度表征。了解电离辐射对细胞的影响是基础生物学的重要组成部分。染色体异常是复杂的细胞终点，由电离辐射产生，并提供有关DNA损伤产生、修复和错误修复的基本机制的信息。在应用放射生物学的主要领域，包括癌症风险评估、估计放射治疗过程中的细胞死亡和生物剂量学(即判断个人过去的辐射暴露，例如在辐射事故或宇航员执行任务后)，畸变也有很大影响。由于当前的兴趣增加和实验技术的改进，已经有大量关于辐射引起的像差的新数据。研究人员使用最先进的数学和计算机方法研究了染色体异常形成的潜在生物物理学。他的方法区分了目前三种像差形成的分子模型，这三种模型主要是在尚未进行实验测量的情况下预测辐射损害水平所需的，例如剂量太低，在实验室分析中很难处理，但可能会引起大规模人口的关注。数学和计算机建模是一种相对便宜的方式，可以最大限度地利用从快速增长的数据库和帮助指南实验中获得的生物信息。