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电离辐射会产生染色体畸变，穿越和大规模改组染色体。 使用荧光原位杂交技术来绘画各种颜色的各种颜色揭示了各种各样的简单和复杂的畸变，每种颜色都表明了两种或莫雷德纳的双链断裂，其中涉及一次过度误导。 研究者对当前数据对畸变的生物物理意义进行了计算，以及与沿染色体的DNA双链断裂的螺栓纤维凝胶 - 电泳数据有关，与早期阶段的结构阶段有关。 比较了三种用于DNA断裂的基本分子模型。 这种误解有很多组合功能，以至于系统地解释广泛的，详尽的当前数据需要定理，方程和计算机模拟。 主要方法是：（1）概率理论和稳定过程理论的标准结果，主要是在泊松群集点上； （2），扩展CAS（染色体异常模拟器）计算机软件。 继续与全球许多不同的经验集团合作。 假设断裂诱导和虚假措施的模型可以表征合理的准确性，仅使用两个可调参数，许多不同类型的畸变的特性频率以及对染色体臂棒基因组含量的依赖性。 了解电离辐射对细胞ISAN的影响ISAN的重要部分。 染色体畸变复合物细胞终点，由电离化辐射产生，并且对DNA损伤生产，修复和虚假的基本机制产生了丰富的信息。 在应用放射生物学的主要领域，包括风险评估，估计放射治疗期间的细胞杀死和生物测量法（即判断辐射对辐射的暴露于辐射事故后，辐射事故或Anastronaut的任务后，判断辐射暴露于辐射时，估计细胞杀死，估计细胞杀死，也可以在辐射疗法或Anastronaut的任务后判断，畸变也是鲁棒的。 由于当前的兴趣增加和敬酒的实验技术，因此在辐射引起的畸变方面泛滥成灾。 研究者使用最先进的数学和计算机方法研究了染色体畸变形成的生物物理学。 HISMethods区分了三种当前的分子模型形成的分子模型，这些模型主要是为了预测尚未经过审查的情况下预测辐射损伤的效果，例如剂量太低，无法容易被易于探索的内置分析，但对于可能的大型人群可能存在。 数学和计算机建模是可观的廉价方法，可以从快速增加的数据库中最大化生物学信息和帮助指导实验。