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.

萨克斯9971169 电离辐射可引起染色体畸变、贯穿断裂和大规模的染色体重组。 利用荧光原位杂交技术将不同的染色体涂上不同的颜色，揭示了丰富多样的简单和复杂的畸变，每个畸变都表明在一个整体的错误修复反应中涉及两个或多个DNA双链断裂。 研究者对畸变的当前数据和与畸变形成的早期阶段相关的DNA双链断裂沿沿着染色体聚集的脉冲场凝胶电泳数据的生物物理意义进行计算。 比较了DNA断裂重接的三种基本分子模型。 有这么多的组合的可能性，这种错误的连接，定理，方程，和计算机模拟需要系统地解释广泛的，精心制作的电流数据。 主要方法有：（1）适当地采用概率论和随机过程理论的标准结果，主要是Poisson簇点过程的结果，（2）扩充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团体的合作仍在继续。 断裂诱导和错误修复的随机性模型可以以合理的准确度表征，仅使用两个可调参数，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含量的依赖性。 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。 染色体畸变是一种复杂的细胞终点，由电离辐射大量产生，并提供有关DNA损伤产生、修复和错误修复的基本机制的信息。 畸变也与应用放射生物学的主要领域密切相关，包括癌症风险评估、估计放射治疗过程中的细胞杀伤和生物剂量测定（即判断个人过去受到的辐射，例如在辐射事故或宇航员使命之后）。 由于目前的兴趣增加和实验技术的改进，出现了大量关于辐射诱导像差的新数据。 研究人员使用最先进的数学和计算机方法研究染色体畸变形成的基本生物物理学。 他的方法区分了目前三种畸变形成的分子模型，这些模型主要用于预测尚未实验测量的情况下的辐射损伤水平，例如剂量太低，无法在实验室分析中容易处理，但仍然可能对大人群产生影响。 数学和计算机建模是一种相对廉价的方法，可以最大限度地利用从快速增长的数据库中获得的生物信息，并帮助指导实验。