BIOMATHEMATICAL APPROACHES TO CANCER

描述（改编自申请人摘要）：本研究的重点 将是基于健全的生物定量方法的发展 致癌物质中间病变分析原则 通路 这种病变通常出现在实验性癌变模型中 系统，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的 生物学参数如起始速率和细胞增殖速率 细胞的分裂和死亡。 此外，基于生物 定量分析应导致假设的产生， 在未来的实验中测试。 经典的启蒙-促进 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，在显微镜下制成二维切片。 因此，必须采用体视学方法， 三维图像。 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，而不必 牺牲动物。 因此，重复的观察是在同一 动物 这导致了相关纵向的统计问题， 意见。 癌发生的两突变克隆扩张模型将形成 这项工作的基础。 该模型假设了两个限速步骤， 恶性肿瘤的途径，并明确考虑细胞分裂和细胞 死亡，有自然的解释， 化学致癌的启动-促进-进展模式。 的 第一个限速事件被鉴定为起始，克隆 启动细胞的扩增与促进，和第二限速 事件进展。 计划实施四个具体项目。 第一 该项目与更现实的生物融合有关 假设比迄今已被用于两个突变克隆 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。 第二个项目是 试图放松强立体的假设，已在 改变的肝病灶的分析。 具体来说，假设 这些焦点是完美的球体将被松弛。 这将允许 两突变模型在实验系统中的应用，例如 肾脏和胰腺，其中假设球形病灶是 站不住脚 第三个项目将制定量化方法， 分析非常小的改变肝病灶，目前正在 通过开发适当的标记物进行实验研究。 第四个项目将制定应用 两突变克隆扩展模型对相关分析 中间病变的纵向数据，如乳头状瘤， 小鼠皮肤绘画实验。

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.