Mathematical Sciences: Chromosome Geometry and Chromosome Aberrations

数学科学：染色体几何和染色体畸变

• 批准号: 9532055
• 负责人: Rainer Sachs
• 金额: $ 15万
• 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: 1996
• 资助国家: 美国
• 起止时间: 1996-08-15 至 2000-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9532055&HistoricalAwards=false
• 关键词: Mathematical; Sciences; Chromosome; Geometry; Aberrations

Sachs 9532055 The investigator models chromosome aberrations in live mammalian cells, emphasizing implications for large-scale chromosome geometry and for the biology of ionizing radiation damage. He analyzes formation of chromosome aberrations after induction of DNA double strand breaks by radiation during the interphase part of the cell cycle, using probabilistic models for DNA geometry, motion, and reactions at the macromolecular level. For example, one area concerns the combinatorics and kinetics of illegitimate recombinations, involving the exchange of fragments between several different chromosomes. Polymer models are used for large-scale chromosome structure and motion. Statistical questions arise when very detailed experimental information about specific individual chromosomes is made available by modern fluorescent in situ hybridization techniques; these he addresses by extending already developed Monte-Carlo simulations. The study involves developing computer algorithms, explicitly solving stochastic process models, and collaborating with experimental groups. Ionizing radiation damage to chromosomes is being studied mathematically. When ionizing radiation hits cells, as occurs for example in tumor radiotherapy or radiation accidents, one gets breakage and large-scale reshuffling of DNA molecules. The resulting chromosome aberrations have been implicated as symptoms or causes of most major radiobiological effects. They are especially important in biodosimetry, the estimation of past exposure to radiation dose by looking at residual cellular damage. They are also a window on fundamental biology because they are influenced by, and symptomatic of, chromosome geometry and motion. Recent developments, whereby specific human chromosomes can be "painted" different colors, have dramatically increased the amount of information obtained from aberration studies. A very rich and colorful variety of aberrations can now be observed. Trying to und erstand the number and kind of reshufflings one sees leads to mathematically nontrivial problems, amenable to computer simulations or "pen and paper" calculations. The simulations and calculations are being carried out under the grant. The results allow systematic comparisons of cellular radiation damage effects observed by different laboratories using different chromosome painting schemes. In addition, mechanistic modeling of how chromosome aberrations evolve in time is helping to attack the main mystery of radiobiology: how to extrapolate from the larger doses needed for statistically significant experimental results to the much smaller doses relevant to risk estimates for large human populations subjected to radiation from environmental or man-made sources.

SACHS 9532055研究者模拟活哺乳动物细胞中的染色体畸变，强调了对大型染色体几何形状和电离辐射损伤的生物学的影响。 他使用概率模型在大分子分子水平的DNA几何形状，运动和反应中，分析了在细胞周期的相间部分中通过辐射诱导DNA双链在辐射部分中的染色体畸变的形成。 例如，一个领域涉及非法重组的组合和动力学，涉及几种不同染色体之间碎片的交换。 聚合物模型用于大规模的染色体结构和运动。 当现代荧光原位杂交技术提供有关特定单个染色体的非常详细的实验信息时，就会出现统计问题；他通过扩展已经开发了蒙特卡洛模拟来解决这些问题。 该研究涉及开发计算机算法，明确求解随机过程模型，并与实验组合作。 对染色体的电离辐射损害正在数学上研究。 当电离辐射击中细胞时，例如在肿瘤放射疗法或辐射事故中发生的情况时，人们会发生断裂并大规模改组DNA分子。 由此产生的染色体畸变被认为是大多数主要放射生物学作用的症状或原因。 它们在生物测量法中尤其重要，即通过查看残留的细胞损伤来估计过去暴露于辐射剂量的估计。 它们也是有关基本生物学的窗口，因为它们受染色体几何形状和运动的影响和症状。 最近的发展，可以将特定的人类染色体“涂成”不同的颜色，从而大大增加了从畸变研究获得的信息量。 现在可以观察到非常丰富和丰富多彩的畸变。 试图说明人们看到的数量和类型会导致数学上的非平凡问题，这是计算机模拟或“笔和纸”计算的。 模拟和计算是根据赠款进行的。 结果允许使用不同染色体绘画方案观察到的不同实验室观察到的细胞辐射损伤效应的系统比较。 此外，染色体畸变如何发展的机理模型正在帮助攻击放射生物学的主要奥秘：如何从统计上重要的实验结果所需的较大剂量中推断出与较小的剂量相关的较小剂量，该剂量与受环境或人为来源受到辐射的大型人群的风险估计相关。