Molecular Interaction Maps and Analysis of Bioregulatory Networks

这个项目是在Kohn？是LMP的一个小组，由两条研究线组成。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等，2011;Luna， Sunshine等，2011；Chandan等，2012）。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BioPAX交换标准（Demir等人，2010）和系统生物学图形符号（SBGN），该符号是由我们参与的国际联盟开发的（Le Novere， Hucka等人，2009；van Iersel等人，2012）。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。该模型目前正在实验研究中，使用一个可以直接可视化p5转录活性的系统。在另一项研究中，我们创建了一个哺乳动物生物钟的扩展计算模型，该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。使用模型中包含的分子相互作用网络的模拟研究能够概括昼夜节律行为。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。在未来，我们的目标是将这些研究与调节DNA合成和影响细胞生长的细胞周期调节网络的实验表征结合起来。这些研究的结果也可能增加对昼夜节律在包括普通癌症药物在内的治疗药物的毒性和活性中的作用的认识。

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; Chandan et al., 2012). 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 BioPAX exchange standard (Demir et al., 2010) and the systems biology graphical notation (SBGN) that is developed by an international consortium with our participation (Le Novere, Hucka et al. 2009; van Iersel et al., 2012). 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 using a system in which the transcriptional activity of p5 can be directly visualized. In a separate line of study 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. Simulation studies using the molecular interaction network included in the model were able to recapitulate circadian behavior. Development and analysis of this model will provide insights into the regulation of circadian rhythms and the potential role of SIRT1 in cancer biology. In the future we aim to combine these studies with experimental characterization of cell cycle regulatory networks that modulate DNA synthesis and affect cell growth. Results from these studies may also add to knowledge on the role of circadian rhythms on the toxicity and activity of therapeutics, including common cancer drugs.