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，以及我们拟议的案例综合癌症生物学计划（ICBP）的广泛，长期目标，是建立一个由系统科学家和癌症生物学家组成的完全集成的跨学科团队，可以使用系统方法解决癌症的复杂生物学问题。这项工作是建立在凯斯医学院的癌症研究强项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。该项目将产生一个预测的脱氧核苷酸代谢的计算机模型，这将促进未来治疗错配修复缺陷（MMR-）恶性肿瘤的药物和辐射剂量时间过程优化。这些项目将研究两种选择性杀死MMR缺陷细胞的基本方法。在一种方法（项目1）中，针对甲基化沉默或基因突变导致的MMR缺陷细胞；在另一种方法（项目2）中，仅靶向甲基化沉默的MMR缺陷细胞。在这两种方法中，策略都是优先将药物积累到MMR缺陷细胞的DNA中。在第一种方法中，IdUrd优先在MMR缺陷细胞的DNA中积累，在适当数量的掺入后，细胞暴露于辐射中以选择性地杀死MMR细胞。在第二种方法中，首先使用FdCyd选择性地将FdCyd装载到由于甲基化而导致MMR缺陷的细胞的DNA中，然后使用dH4Urd（胞苷脱氨酶抑制剂）将FdCyd重定向到DNA中，在那里它作为一种去甲基化剂逆转MMR能力，从而产生DNA双链断裂（dsb）的灾难性spike。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，以及对回收和从头开始的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中生成脱氧核苷酸代谢模型，并将其公开提供R和系统生物学标记语言（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）。完成这些项目将为后续的转化性癌症研究提供必要的基础。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，能够将癌症作为复杂生物系统的问题进行研究。

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.