BIOMATHEMATICAL APPROACHES TO CANCER

癌症的生物数学方法

• 批准号: 6172408
• 负责人: SURESH H MOOLGAVKAR
• 金额: $ 17.77万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6172408
• 关键词: biological models; carcinogenesis; cell cycle; cell proliferation; computer data analysis; laboratory mouse; liver neoplasms; longitudinal animal study; mathematical model; method development; model design /development; morphology; statistics /biometry; time resolved data

DESCRIPTION (Adapted from applicant's abstract): The focus of this research will be on development of quantitative methods based on sound biological principles for the analyses of intermediate lesions on the carcinogenic pathway. Such lesions commonly arise in experimental carcinogenesis model systems, such as the mouse skin and rodent liver initiation-promotion systems. The ultimate goal of the analyses is the estimation of critical biological parameters such as the rate of initiation and the rates of cell division and death of initiated cells. Additionally, biologically-based quantitative analyses should lead to the generation of hypotheses to be tested in future experiments. The classical initiation-promotion experimental models, namely the mouse skin and the rodent liver systems, provide unique challenges to the analyst. In the rodent liver system, quantitative observations on three-dimensional objects, the altered hepatic foci, are made in two-dimensional sections under the microscope. Stereological methods must then be employed in order to reconstruct the three-dimensional picture. In the mouse skin system, premalignant lesions, the papillomas, and malignant lesions are directly visible without having to sacrifice the animal. Thus repeated observations are made on the same animal. This leads to the statistical problem of correlated longitudinal observations. The two-mutation clonal expansion model of carcinogenesis will form the basis of this work. This model, which postulates two rate-limiting steps on the pathway to malignancy and explicitly considers cell division and cell death, has natural interpretation within the initiation-promotion-progression paradigm of chemical carcinogenesis. The first rate-limiting event is identified with initiation, the clonal expansion of initiated cells with promotion, and the second rate-limiting event with progression. Four specific projects are planned. The first project has to do with incorporation of more realistic biological assumptions than have hitherto been used into the two-mutation clonal expansion model. In particular, more realistic mathematical descriptions of cell proliferation kinetics will be investigated. The second project will attempt to relax the strong stereological assumptions that have been made in the analyses of altered hepatic foci. Specifically, the assumption that these foci are perfect spheres will be relaxed. This will allow the application of the two-mutation model to experimental systems, such as the kidney and the pancreas, in which the assumption of spherical foci is untenable. The third project will develop quantitative methods for the analyses of very small altered hepatic foci, which are now being experimentally investigated with the development of the appropriate markers. The fourth project will develop methods for the application of the two-mutation clonal expansion model to the analyses of correlated longitudinal data on intermediate lesions, such as the papillomas arising in mouse skin painting experiments.

描述（改编自申请人的摘要）：本研究的重点 将致力于开发基于合理生物学的定量方法 致癌中间病变分析原则 途径。 这种病变通常出现在实验性致癌模型中 系统，例如小鼠皮肤和啮齿动物肝脏启动促进 系统。 分析的最终目标是估计关键 生物参数，例如起始速率和细胞速率 启动细胞的分裂和死亡。 此外，基于生物学 定量分析应导致假设的产生 在未来的实验中进行测试。 经典的启动-提升 实验模型，即小鼠皮肤和啮齿动物肝脏系统， 给分析师带来了独特的挑战。 在啮齿动物的肝脏系统中， 对三维物体的定量观察，改变的肝脏 焦点是在显微镜下制成二维切片的。 然后必须采用体视学方法来重建 三维图片。 在小鼠皮肤系统中，癌前病变， 乳头状瘤和恶性病变是直接可见的，无需 牺牲动物。 因此，对同一事物进行重复观察 动物。 这导致了相关纵向的统计问题 观察。 致癌作用的二突变克隆扩增模型将形成 这项工作的基础。 该模型假设有两个速率限制步骤 恶性途径并明确考虑细胞分裂和细胞 死亡，有自然的解释 化学致癌作用的起始-促进-进展范式。 这 第一个限速事件被确定为起始，克隆 启动细胞的扩张与促进，以及第二个速率限制 事件有进展。 规划了四个具体项目。 第一个 该项目与结合更现实的生物 迄今为止已用于二突变克隆的假设 扩展模型。 特别是，更现实的数学描述 将研究细胞增殖动力学。 第二个项目将 试图放松已经做出的强烈的体视假设 改变肝病灶的分析。 具体来说，假设 这些焦点是完美的球体，会被放松。 这将允许 将二突变模型应用于实验系统，例如 肾脏和胰腺，其中球形病灶的假设是 站不住脚的。 第三个项目将开发定量方法 对非常小的改变的肝脏病灶进行分析，这些病灶现在正在 通过开发适当的标记进行实验研究。 第四个项目将开发应用方法 用于相关分析的双突变克隆扩展模型 中间病变的纵向数据，例如出现在 小鼠皮肤绘画实验。