BIOMATHEMATICAL APPROACHES TO CANCER

描述(改编自申请者摘要)：本研究的重点 将致力于发展基于健全生物学的定量方法 致癌物中间病变分析原则 路径。这种损害通常发生在实验性的致癌模型中。 系统，如小鼠皮肤和啮齿动物肝脏的启动促进 系统。分析的最终目标是估计关键的 生物学参数，如起始率和细胞率 启动细胞的分裂和死亡。此外，基于生物的 量化分析应该导致假设的产生 在未来的实验中进行了测试。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， 向分析师提出独特的挑战。在啮齿动物的肝脏系统中， 肝脏病变三维物体的定量观察 焦点，是在显微镜下制成的二维切片。 然后必须使用体视学方法来重建 三维图。在小鼠皮肤系统中，癌前病变， 乳头状瘤和恶性病变可以直接看到，而不必 献祭这只动物。因此，对同一问题进行了反复的观察 动物。这导致了纵向相关的统计问题 观察。 致癌的双突变克隆扩增模型将形成 这项工作的基础。该模型假设了两个速率限制步骤 致癌途径，明确考虑了细胞分裂和细胞 死亡，有自然的解释，在 化学致癌的启动-促进-进展范式。这个 第一个速率限制事件被识别为启动、克隆 通过促进启动细胞的扩展，以及第二速率限制 有进展的事件。计划开展四个具体项目。第一 该项目与融入更现实的生物学有关 比迄今用于双突变克隆的假设更多 扩张模式。特别是，更真实的数学描述 将对细胞增殖动力学进行研究。第二个项目将 尝试放松已在 肝脏占位病变的分析。具体地说，假设 这些焦点是完美的球体，会放松的。这将允许 双突变模型在实验系统中的应用 肾脏和胰腺，其中球形病灶的假设是 站不住脚。第三个项目将开发定量方法，用于 对非常小的改变的肝脏病灶的分析，现在正在 通过实验研究开发了合适的标记物。 第四个项目将开发应用 双突变克隆扩展模型在相关分析中的应用 中间病变的纵向数据，例如 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.