Complex Systems & Control of MMR-Deficient Cells

复杂系统

• 批准号: 7503929
• 负责人: TIMOTHY J KINSELLA
• 金额: $ 18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7503929
• 关键词: Address; Biological; Cancer Biology; Cells; Competence; Complex; Computer Simulation; Cytidine Deaminase Inhibitor; DNA; DNA Double Strand Break; Data Collection; Dose; Educational Activities; Engineering; Future; Gene Mutation; Goals; Language; Malignant Neoplasms; Metabolism; Methylation; Mismatch Repair; Modeling; Oncologist; Pathway interactions; Pharmaceutical Preparations; Process; Radiation; Research; Schools; Scientist; System; Systems Analysis; Systems Biology; Systems Theory; Testing; Time; Validation; Work; anticancer research; data modeling; killings; medical schools; model development; programs; research study

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.

描述（由申请人提供）：拟议的计划活动的目的以及我们提议的病例综合癌症生物学计划（ICBP）的广泛长期目标是开发一个完全综合的系统科学家和癌症生物学家的跨学科团队，可以使用系统方法解决癌症的复杂生物学问题。 这项努力是建立在案例工程学院系统理论和数学控制中的医学和开创性研究中的癌症研究方面建立的。 这项工作的范围由五个集成项目组成，包括研究，数据和模型共享以及教育活动。 这些项目将在脱氧核苷酸代谢的计算机模型中产生预测性，该模型将促进药物和辐射剂量的时间课程在未来的不匹配修复缺陷（MMR-）恶性肿瘤的疗法中的优化。 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MMR缺陷的细胞是针对甲基化或遗传突变的。在另一种方法（项目2）中，仅甲基化沉默的MMR缺陷细胞是针对的。 在这两种方法中，该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，并在适当的掺入后，将细胞暴露于辐射中以选择性地杀死MMR-细胞。 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 （DSB）。 通过涉及模型开发和系统分析，实验和数据收集，模型测试和验证的迭代过程，以及对挽救和从头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中提供脱氧核苷酸代谢模型，并在r上公开使用RENGEN和SYSTEM IT ONDER IT COMPAL IT COMPAL IT COMPAL IT OND PROCVEN IT OND PROCVEN（Project 4）。 为了教育肿瘤学家和工程师，我们将开发综合癌症生物学的研究生级课程序列（项目5）。 完成这些项目将产生随后的转化癌症研究所需的基础。 这项为期三年的项目完成后，我们将建立一个强大的跨学科团队，该团队将能够将癌症研究作为复杂生物系统的问题进行推进。