Molecular Interaction Maps and Analysis of Bioregulatory Networks

本项目是与LMP的科恩？S博士团队密切合作完成的，包括两个研究方向。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(露娜，Karac等人。2011年；露娜，阳光等人。2011年；Chanda等人，2012年)。这些工具应该使开发人员更容易构建与MIM相关的软件，用户创建和编辑MIM图表，并且还有助于弥合MIM中发现的功能和相关符号之间的差异，例如BioPAX交换标准(Demir等人，2010)和由我们参与的国际财团开发的系统生物学图形符号(SBGN)(Le Novere，Hucka等人。2009年；van Iersel等人，2012年)。我们使用MIMs作为细胞调控网络的数学建模的基础，以努力阐明调节细胞增殖的基本反馈机制。我们调查的第一个网络描述了MDM2和MDMX对肿瘤抑制因子P53的调节，以响应DNA损伤(Kim，Aladjem等人)。2010)。简化的网络模型是根据详细的分子相互作用图(MIM)得出的，该图展示了四条连贯的DNA损伤反应途径。结果提示，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。这些研究使我们认为MDMX在p53对DNA损伤的反应中可能发挥了作用。这个模型目前正在进行实验研究，使用的系统可以直接显示P5的转录活性。在另一项研究中，我们创建了一个哺乳动物昼夜节律的扩展计算模型，该模型强调染色质重塑和代谢途径在调节昼夜节律中的作用。这个模型结合了最近的实验证据，表明依赖于烟酰胺腺嘌呤二核苷酸(NAD+)的组蛋白去乙酰基酶SIRT1在调节昼夜节律中发挥了作用。使用模型中包含的分子相互作用网络进行的模拟研究能够概括昼夜行为。这个模型的开发和分析将为调节昼夜节律和SIRT1在癌症生物学中的潜在作用提供见解。在未来，我们的目标是将这些研究与细胞周期调控网络的实验特征相结合，这些网络调节DNA合成并影响细胞生长。这些研究的结果也可能增加关于昼夜节律对包括常见抗癌药物在内的治疗药物的毒性和活性的作用的知识。创建和编辑分子相互作用图的工具对于接受和采用该方法是必不可少的。今年，我们扩大了对符号可用的工具支持的保留范围，并对SBGN的支持做出了贡献，SBGN是社区努力为系统生物学开发图形符号的努力。

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. Tools to create and edit molecular interaction maps are essential for the acceptance and adoption of the methodology. This year we have expanded the repertoire of tool support available for the notation as well as contributed to the support of SBGN, a community effort to develop a graphical notation for systems biology.