Molecular Interaction Maps and Analysis of Bioregulatory Networks

分子相互作用图谱和生物调节网络分析

• 批准号: 8349049
• 负责人: mirit aladjem
• 金额: $ 12.36万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349049
• 关键词: Antineoplastic Agents; Binding; Bioinformatics; Cancer Biology; Cell Proliferation; Circadian Rhythms; Collaborations; Computer Simulation; Computer software; Computers; DNA Damage; Data; Development; Devices; Electronics; Exhibits; Extensible Markup Language; Feedback; Goals; Histone Deacetylase; International; Investigation; Knowledge; Language; Light; Maps; Metabolic Pathway; Methods; Modeling; Molecular; Nicotinamide adenine dinucleotide; Pathway interactions; Protein p53; Regulation; Role; Scientist; Systems Biology; Therapeutic; Toxic effect; Validation; base; chromatin remodeling; circadian pacemaker; insight; mathematical model; microbial alkaline proteinase inhibitor; network models; response; tool

This project is performed in close collaboration with Dr. Kohn's group in LMP and consists of two lines of study. First, we have recently developed and released several tools for creating and editing MIM diagrams (Luna, Karac et al. 2011; Luna, Sunshine et al. 2011). These tools should make it easier for developers to build MIM-related software, users to create and edit MIM diagrams, and also, help bridge differences between features found in MIM and related notations, such as the systems biology graphical notation (SBGN) that is developed by an international consortium with our participation (Le Novere, Hucka et al. 2009). In a separate line of study, we use MIMs as a basis for mathematical modeling of cellular regulatory networks in an effort to shed light on basic feedback mechanisms that modulate cell proliferation. The first network we have investigated describes the regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage (Kim, Aladjem et al. 2010). The simplified network model was derived from a detailed molecular interaction map (MIM) that exhibited four coherent DNA damage response pathways. The results suggest that MdmX may amplify or stabilize DNA damage-induced p53 responses via non-enzymatic interactions. These studies led us to suggest a possible role of MdmX in the response of p53 to DNA damage. This model is currently under experimental investigation. Recently we have created an extended computational model of a mammalian circadian clock that emphasizes the roles of chromatin remodeling and metabolic pathways on the regulation of circadian rhythms. This model incorporates recent experimental evidence suggesting a role for the nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase SIRT1 in regulating circadian rhythms. Development and analysis of this model will provide insight into the regulation of circadian rhythms and the potential role of SIRT1 in cancer biology. Results from this model may also add to knowledge on the role of circadian rhythms on the toxicity and activity of therapeutics, including common cancer drugs. Kim, S., M. I. Aladjem, et al. (2010). "Predicted functions of MdmX in fine-tuning the response of p53 to DNA damage." PLoS Comput Biol 6(2): e1000665. Le Novere, N., M. Hucka, et al. (2009). "The Systems Biology Graphical Notation." Nat Biotechnol 27(8): 735-741. Luna, A., E. I. Karac, et al. (2011). "A formal MIM specification and tools for the common exchange of MIM diagrams: an XML-Based format, an API, and a validation method." BMC Bioinformatics 12(1): 167. Luna, A., M. L. Sunshine, et al. (2011). "PathVisio-MIM: PathVisio plugin for creating and editing Molecular Interaction Maps (MIMs)." Bioinformatics 27(15): 2165-2166.

该项目与Kohn博士在LMP的小组密切合作，包括两条研究路线。首先，我们最近开发并发布了几个用于创建和编辑MIM图的工具（Luna, Karac et al. 2011; Luna, Sunshine et al. 2011）。这些工具应该使开发人员更容易构建与MIM相关的软件，用户更容易创建和编辑MIM图，并且还有助于在MIM和相关符号中发现的功能之间建立桥梁，例如由我们参与的国际联盟开发的系统生物学图形符号（SBGN） （Le Novere, Hucka et al. 2009）。在另一项单独的研究中，我们使用MIMs作为细胞调节网络数学建模的基础，以阐明调节细胞增殖的基本反馈机制。我们研究的第一个网络描述了Mdm2和MdmX对肿瘤抑制因子p53的调控，以应对DNA损伤（Kim, Aladjem et al. 2010）。简化的网络模型来源于详细的分子相互作用图（MIM），显示了四种连贯的DNA损伤反应途径。结果表明，MdmX可能通过非酶相互作用放大或稳定DNA损伤诱导的p53反应。这些研究使我们提出MdmX在p53对DNA损伤的反应中可能起的作用。这个模型目前正在实验研究中。最近，我们创建了一个扩展的哺乳动物生物钟计算模型，强调了染色质重塑和代谢途径在昼夜节律调节中的作用。该模型结合了最近的实验证据，表明烟酰胺腺嘌呤二核苷酸（NAD+）依赖性组蛋白去乙酰化酶SIRT1在调节昼夜节律中的作用。该模型的开发和分析将有助于深入了解昼夜节律的调节以及SIRT1在癌症生物学中的潜在作用。该模型的结果也可能增加对昼夜节律在治疗药物（包括普通癌症药物）的毒性和活性中的作用的认识。Kim， S.， M. I. Aladjem，等（2010）。“预测MdmX在微调p53对DNA损伤的反应中的功能。”计算机工程学报，6(2):663 - 668。Le Novere， N.， M. Hucka等（2009）。《系统生物学图解法》生物工程学报，27(8):735-741。卢娜，A., e.i. Karac，等（2011）。一个正式的MIM规范和工具，用于MIM图的公共交换：基于xml的格式、API和验证方法。中国生物医学工程学报，12(1):393。卢娜，A.， M. L. Sunshine，等（2011）。PathVisio- mim：用于创建和编辑分子相互作用图（MIMs）的PathVisio插件。生物信息学27(15):2165-2166。