Fathead minnow steroidogenesis: in silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk.
Fathead minnow steroidogenesis: in silico analyses reveals tradeoffs between nominal target efficacy and robustness to cross-talk.
复制标题
DOI：
10.1186/1752-0509-4-89
复制
发表时间：
2010-06-28
影响因子：
--
通讯作者：
Doyle FJ 3rd
中科院分区：
文献类型：
--
作者：
Shoemaker JE;Gayen K;Garcia-Reyero N;Perkins EJ;Villeneuve DL;Liu L;Doyle FJ 3rd
解释蛋白质和基因组数据是预测生态毒理学中的一个主要挑战，可以通过系统生物学的方法来解决。数学模型提供了一个组织平台来巩固蛋白质动力学与可能的基因组调控。在这里，我们开发了一种肥头小鱼Pimephales proelas(FHM)的卵巢类固醇生成模型，以评估在基因芯片研究中观察到的类固醇生成的可能转录调节。该模型是根据文献资料开发的，整合了关键信号成分(G蛋白和PKA激活)及其对类固醇产生的后续影响。该模型正确地预测了鱼暴露于Fadrozole(一种特定的芳香酶抑制剂)时雌二醇和睾酮的轨迹行为，但未能预测暴露后一周发生的类固醇激素行为以及去掉应激源时类固醇水平的增加。在体内微阵列数据暗示了三种调节模式，可能解释了在净化阶段(当应激源被移除时)类固醇的过度产生：P450酶上调，抑制素下调，以及黄体生成素受体上调。模拟研究和敏感性分析被用来评估每个病例作为内分泌应激的可能补偿来源。对芯片数据中观察到的睾酮和雌二醇调节反应的模拟研究支持这样的假设，即FHM类固醇生成网络通过调节卵巢网络对来自下丘脑和垂体的全局信号的敏感性来补偿内分泌应激。促黄体激素受体调节的模型预测与纯化和体外数据一致。这些结果挑战了系统生物学中网络阐明的传统方法。一般来说，网络中最敏感的相互作用是为了进一步阐明，但微阵列证据表明，类固醇合成网络的动态平衡调节可能由中等敏感的相互作用维持。我们假设，在确定可能的调节点时，有效的网络阐明必须同时考虑目标的敏感性以及目标对生物噪声(在这种情况下，对串扰)的稳健性。
Interpreting proteomic and genomic data is a major challenge in predictive ecotoxicology that can be addressed by a systems biology approach. Mathematical modeling provides an organizational platform to consolidate protein dynamics with possible genomic regulation. Here, a model of ovarian steroidogenesis in the fathead minnow, Pimephales promelas, (FHM) is developed to evaluate possible transcriptional regulation of steroid production observed in microarray studies. The model was developed from literature sources, integrating key signaling components (G-protein and PKA activation) with their ensuing effect on steroid production. The model properly predicted trajectory behavior of estradiol and testosterone when fish were exposed to fadrozole, a specific aromatase inhibitor, but failed to predict the steroid hormone behavior occurring one week post-exposure as well as the increase in steroid levels when the stressor was removed. In vivo microarray data implicated three modes of regulation which may account for over-production of steroids during a depuration phase (when the stressor is removed): P450 enzyme up-regulation, inhibin down-regulation, and luteinizing hormone receptor up-regulation. Simulation studies and sensitivity analysis were used to evaluate each case as possible source of compensation to endocrine stress. Simulation studies of the testosterone and estradiol response to regulation observed in microarray data supported the hypothesis that the FHM steroidogenesis network compensated for endocrine stress by modulating the sensitivity of the ovarian network to global cues coming from the hypothalamus and pituitary. Model predictions of luteinizing hormone receptor regulation were consistent with depuration and in vitro data. These results challenge the traditional approach to network elucidation in systems biology. Generally, the most sensitive interactions in a network are targeted for further elucidation but microarray evidence shows that homeostatic regulation of the steroidogenic network is likely maintained by a mildly sensitive interaction. We hypothesize that effective network elucidation must consider both the sensitivity of the target as well as the target's robustness to biological noise (in this case, to cross-talk) when identifying possible points of regulation.
登录
查看更多内容
影响因子：
64.8
作者：
Barkai, N;Leibler, S
通讯作者：
Leibler, S
影响因子：
3.8
作者：
Ankley, GT;Kahl, MD;Leino, RL
通讯作者：
Leino, RL
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1073/pnas.0904837106
发表时间：
2009-07-07
影响因子：
11.1
作者：
Mirsky, Henry P.;Liu, Andrew C.;Doyle, Francis J., III
通讯作者：
Doyle, Francis J., III
影响因子：
5.8
作者：
Bagheri, Neda;Stelling, Joerg;Doyle, Francis J., III
通讯作者：
Doyle, Francis J., III