Complex Systems & Control of MMR-Deficient Cells

描述(由申请人提供)：拟议的规划活动的目标，以及我们拟议的病例整合癌症生物学计划(ICBP)的广泛、长期目标，是发展一支由系统科学家和癌症生物学家组成的完全整合的跨学科团队，能够使用系统方法解决癌症的复杂生物学问题。这一努力是建立在凯斯医学院癌症研究优势和凯斯工程学院在系统理论和数学控制方面的开创性研究的基础上的。这项工作的范围由五个综合项目组成，包括研究、数据和模型共享以及教育活动。这些项目将产生一种可预测的脱氧核苷酸代谢的电子计算机模型，这将有助于在未来错配修复缺陷(MMR-)恶性肿瘤的治疗中优化药物和辐射剂量时间进程。这些项目将研究选择性杀死MMR缺陷细胞的两种基本方法。在一种方法(项目1)中，目标是由于甲基化沉默或基因突变而导致的MMR缺陷细胞；在另一种方法(项目2)中，仅针对甲基化沉默的MMR缺陷细胞。在这两种方法中，策略都是优先将药物累积到MMR缺陷细胞的DNA中。在第一种方法中，IdUrd优先积聚在MMR缺陷细胞的DNA中，在适当数量的掺入后，细胞暴露于辐射中，选择性地杀死MMR-细胞。在第二种方法中，FdCyd首先被用来选择性地将FdUrd装载到由于甲基化而导致的MMR缺陷细胞的DNA中，在充分装载之后，dH4Urd(胞苷脱氨酶的抑制剂)被用来将FdCyd重定向到DNA中，在那里它充当去甲基化试剂，逆转MMR的活性，从而产生灾难性的DNA双链断裂(DSB)尖峰。通过一个迭代过程，包括模型开发和系统分析、实验和数据收集、模型测试和验证，以及对回收和从头合成脱氧核苷酸合成途径之间的协调和控制的详细研究(项目3)，我们将在R中产生一个脱氧核苷酸代谢模型，并以R和系统生物学标记语言公开提供(项目4)。为了培养肿瘤学家和工程师，我们将开发一个研究生水平的综合癌症生物学课程序列(项目5)。完成这些项目将产生后续转化型癌症研究所需的积木。在这个为期三年的项目完成后，我们将发展一支强大的跨学科团队，能够推动癌症作为复杂生物系统问题的研究。

DESCRIPTION (provided by applicant): The objective of the proposed planning activity, and the broad, long-term goal of our proposed Case Integrative Cancer Biology Program (ICBP), is to develop a fully integrated interdisciplinary team of systems scientists and cancer biologists that can address the complex biological problem of cancer using systems approaches. This effort is being built on a cancer research forte at the Case School of Medicine and pioneering research in systems theory and mathematical control in the Case School of Engineering. The scope of this work is composed of five integrated projects that include research, data and model sharing, and educational activities. The projects will produce a predictive in silico model of deoxynucleotide metabolism that will facilitate drug and radiation dose time course optimizations in future therapies of mismatch repair defective (MMR-) malignancies. The projects will investigate two basic approaches for selectively killing MMR defective cells. In one approach (Project 1), cells that are MMR defective due to either methylation silencing or genetic mutations are targeted; in the other approach (Project 2), only methylation silenced MMR defective cells are targeted. In both approaches, the strategy is to preferentially accumulate drug into DNA of MMR defective cells. In the first approach, IdUrd accumulates preferentially in the DNA of MMR defective cells and after an appropriate amount of incorporation, cells are exposed to radiation to selectively kill MMR- cells. In the second approach, FdCyd is first used to load FdUrd selectively into the DNA of cells MMR defective due to methylation, and after sufficient loading, dH4Urd (an inhibitor of cytidine deaminase) is then used to redirect FdCyd into DNA where it acts as a demethylating agent that reverses MMR competence and thus creates a catastrophic spike of DNA double strand breaks (DSBs). Through an iterative process that involves model development and systems analysis, experimentation and data collection, model testing and validation, and a detailed study of coordination and control between the salvage and de novo deoxynucleotide synthesis pathways (Project 3), we will produce a deoxynucleotide metabolism model in R and make it publicly available in both R and Systems Biology Markup Language (Project 4). To educate oncologists and engineers, we will develop a graduate level course sequence in Integrative Cancer Biology (Project 5). Accomplishing these projects will produce building blocks needed for subsequent translational cancer research studies. At the completion of this three-year project, we will have developed a strong interdisciplinary team that will be capable of advancing the study of cancer as a problem of complex biological systems.