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、染色体断裂和大规模重组。 使用荧光原位杂交技术将各种染色体涂上不同的颜色，揭示出丰富多样的简单和复杂的畸变，每一种畸变都可能表明在一个整体错误修复反应中涉及两个或多个 DNA 双链断裂。 研究人员对当前畸变数据以及与畸变形成早期阶段相关的 DNA 双链断裂簇沿染色体的脉冲场凝胶电泳数据的生物物理影响进行了计算。 比较了 DNA 断裂错误重连的三种基本分子模型。 这种错误重新连接的组合可能性如此之多，以至于需要定理、方程和计算机模拟来系统地解释广泛、详尽的当前数据。 主要方法有：（1）适当采用概率论和随机过程论的标准结果，以泊松聚类点过程为主； (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实验小组的合作仍在继续。 假设断裂诱导和误修复的随机性的模型可以仅使用两个可调节参数（许多不同类型畸变的相对频率及其对所涉及染色体臂的基因组内容的依赖性）以合理的精度来表征。 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。 染色体畸变是复杂的细胞终点，由电离辐射大量产生，并提供有关 DNA 损伤产生、修复和误修复的基本机制的信息。 像差也强烈涉及应用放射生物学的主要领域，包括癌症风险评估、估计放射治疗期间的细胞杀伤和生物剂量测定（即判断个体过去暴露于辐射的情况，例如在辐射事故或宇航员执行任务后）。 由于当前兴趣的增加和实验技术的改进，出现了大量关于辐射引起的像差的新数据。 研究人员利用最先进的数学和计算机方法研究染色体畸变形成的基础生物物理学。 他的方法区分了当前三种像差形成的分子模型，这些模型主要用于预测尚未通过实验测量的情况下的辐射损伤水平，例如剂量太低而难以在实验室分析中处理，但仍然可能引起大量人群的关注。 数学和计算机建模是一种相对便宜的方法，可以最大限度地从快速增长的数据库中获得生物信息并帮助指导实验。