Molecular Interaction Maps and Analysis of Bioregulatory Networks

该项目是与发展治疗分支的Kohn博士密切合作进行的，包括两条研究线。首先，我们已经开发并发布了几种用于创建和编辑MIM图的工具（Luna，Karac等人，2011; Luna，Sunshine等人，2011; Chandan等人，2012年）。这些工具应该使开发人员更容易构建MIM相关软件，用户更容易创建和编辑MIM图，并且还有助于弥合MIM中发现的特征与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联盟开发的系统生物学图形符号（SBGN）（Le Novere，Hucka等人，2009;货车Iersel等人，2012年）。其次，我们使用MIM作为细胞调控网络的数学建模的基础，努力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的调节，以响应DNA损伤（Kim，Aladjem et al. 2010）。在另一项研究中，我们创建了一个以烟酰胺腺嘌呤二核苷酸（NAD+）依赖性组蛋白脱乙酰酶SIRT 1为中心的哺乳动物昼夜节律钟的扩展计算模型（Luna，Aladjem和Kohn，2013）。该模型强调染色质重塑和代谢途径对昼夜节律调节的作用。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，并创建一个模型，其中生物钟的相移响应于遗传毒性应激而发生。该模型的开发和分析将为昼夜节律的调节和SIRT1在癌症生物学中的潜在作用提供见解。在未来，我们的目标是联合收割机这些研究与细胞周期调控网络，调节DNA合成和影响细胞生长的实验表征。这些研究的结果也可能增加关于昼夜节律对治疗药物（包括常见癌症药物）的毒性和活性的作用的知识。

This project is performed in close collaboration with Dr. Kohn at the Developmental Therapeutics Branch and consists of two lines of study. First, we have 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). Second, 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). In a separate line of study we have created an extended computational model of a mammalian circadian clock centered on the the nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase SIRT1 (Luna, Aladjem and Kohn, 2013). This model emphasizes the roles of chromatin remodeling and metabolic pathways on the regulation of circadian rhythms. Simulation studies using the molecular interaction network included in the model were able to recapitulate circadian behavior and create a model in which phase shifting of the circadian clock occurs in response to genotoxic stress.. 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.