Project 2

为了研究癌症，非常强大的现代实验方法~包括高通量方法~，以及 现在使用的是现代统计学/计算机科学方法。癌症时间发展的机械论定量模型， 从非常早期的阶段到临床疾病，都没有得到很好的研究。一位高度 由癌症生物学家、分子生物学家、数学家、 物理学家和计算机科学家已经聚集在一起，致力于研究动态的、机械的癌症发生 模型是如此简约的参数化，以至于具有预测能力。压倒一切的目标是使 通过考虑细胞间相互作用的影响，模型更加真实和可信 致癌。涉及不同的、相互作用的细胞群体和/或肿瘤的作用的时间进程 进展，在漫长的癌症潜伏期中相对较晚的阶段，将被强调。这些现象 最近发现在人类中几乎无处不在的微观肿瘤休眠，以及从 因“开机”而休眠的供血招募将是主要关注的焦点之一。 该团队将在迭代范式下工作：实验数学/计算模型实验， 等。数据将从各种来源收集：体外实验，包括现代高通量结果 对特定蛋白质的深入研究；使用基因工程小鼠的实验；高度发达 成像方法；以及关于人类癌症发病率或死亡率的文献中的结果。其中几个人 项目将涉及电离辐射，这是一种致癌物质，其作用已被非常好地描述为 小的时间和长度尺度，以及整个人类一生和整个生物体，所以它是高度 从总体上讲，这是关于癌症发展的信息。数学方法将包括以下内容：经典 用常微分方程组或偏微分方程组的数学生物学方法；现代离散和 基于多个细胞的离散-连续混合模型，每个细胞被表示为一个可以相互作用的实体 与其他细胞及其微环境按照相对简单的规则，与复杂的批发系统 由这些规则产生的行为；概率“随机过程”模型，因为大多数新的 癌症进化阶段假定起源于单个细胞，面临根除或意外灭绝的风险；以及 多时间尺度计算模型，其中影响受相对较短的时间尺度支配 影响更长时间尺度的癌症进化，反之亦然。

To study cancer, very powerful modern experimental methods ~ including high-throughput approaches ~, and modern statistics/computer-science methods are now used. Mechanistic quantitative models of cancer timedevelopment, from very early stages to clinical disease, have been somewhat less well explored. A highly interdisciplinary, unusually closely interacting team of cancer biologists, molecular biologists, mathematicians, physicists, and computer scientists has been assembled to work toward dynamic, mechanistic carcinogenesis models so parsimoniously parameterized they have predictive capability. The overriding goal is to make the models more realistic and credible by taking into account the influence of intercellular interactions during carcinogenesis. The time-course of effects involving a diverse, interacting cell population and/or of tumor progression, a comparatively late stage in the lengthy cancer latency period, will be emphasized. The phenomena of microscopic tumor dormancy, recently found to be almost ubiquitous in humans, and of emergence from dormancy due to "switching on" of blood supply recruitment will be one main focus. The team will work under an iterative paradigm: experiments a mathematical/computational model a experiments, etc. Data will be gathered from various sources: in vitro experiments, including modern high throughput results and in depth studies of particular proteins; experiments using genetically engineered mice; highly developed imaging approaches; and results in the literature on human cancer incidence or mortality. Several ofthe individual projects will involve ionizing radiation, a carcinogen whose action has been unusually well characterized at very small time and length scales, as well as over a whole human lifetime and for whole organisms, so that it is highly informative about cancer development in general. Mathematical methods will include the following: classic mathematical biology approaches with systems of ordinary or partial differential equations; modern discrete and hybrid discrete-continuous models based on treating many cells, each represented as an entity which can interact with other cells and with its microenvironment according to comparatively simple rules, with complicated wholesystem behavior arising from those rules; probabilistic "stochastic-process" models, needed since most new stages of cancer evolution putatively originate with a single cell, at risk for eradication or accidental extinction; and multi time-scale computational modeling, in which effects governed by comparatively very short time scales influence much longer time-scale cancer evolution and vice-versa.