In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-α-induced apoptosis and proliferation by MAPKs.
In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-α-induced apoptosis and proliferation by MAPKs.
复制标题
DOI：
10.1126/scisignal.2001338
复制
发表时间：
2011-03-22
影响因子：
7.3
通讯作者：
Haigis KM
中科院分区：
文献类型：
--
作者：
Lau KS;Juchheim AM;Cavaliere KR;Philips SR;Lauffenburger DA;Haigis KM
细胞对外部刺激的反应取决于多通路网络信号的动态特征；因此，细胞的行为以一种复杂的方式受到其环境和内在特性的影响。多变量系统分析的方法已经提供了对这些复杂影响的理解，但迄今为止，这只是相对简化的体外细胞培养例子。一个尚未解决的问题是，这些方法能否成功地在体内条件下发挥作用。我们分析了决定肠上皮细胞对促炎细胞因子肿瘤坏死因子α (TNF-α)反应的体内信号网络。我们建立了数据驱动的偏最小二乘判别分析（PLSDA）模型，该模型基于小鼠小肠上皮在全身暴露于TNF-α后的信号传导、凋亡和增殖反应。我们发现细胞外信号调节激酶（ERK）信号轴是不同剂量TNF-α下细胞凋亡时间变化的关键调节剂，以及不同肠道区域增殖反应的空间变化。MEK是ERK上游的一种丝裂原激活的蛋白激酶，其药理抑制可以整体改变信号网络，并根据先验模型预测改变时间和空间表型。我们的研究结果证明了体内信号网络的动态、适应性，并确定了反应表型的自然、组织水平变化，这些变化只能通过定量、多变量计算模型来解卷积。据我们所知，这是第一个将信号网络的计算建模应用于真正的体内系统的研究，它为使用基于系统的方法来理解细胞网络状态的失调如何成为复杂疾病的基础奠定了基础。
Cellular responses to external stimuli depend on dynamic features of multi-pathway network signaling; thus, the behavior is of a cell is influenced in a complex manner by its environment and by intrinsic properties. Methods of multi-variate systems analysis have provided an understanding of these convoluted effects, but to date this has been only for relatively simplified in vitro cell culture examples. An unaddressed question is whether such approaches can be successfully brought to bear on in vivo conditions. We have analyzed the in vivo signaling network that determines the response of intestinal epithelial cells to the pro-inflammatory cytokine tumor necrosis factor α (TNF-α). We built data-driven, partial least-squares discriminant analysis (PLSDA) models based on signaling, apoptotic, and proliferative responses in the mouse small intestinal epithelium after systemic exposure to TNF-α. We identified the extracellular signal–regulated kinase (ERK) signaling axis as a critical modulator of the temporal variation in apoptosis at different doses of TNF-α, as well as the spatial variation in proliferative responses in distinct intestinal regions. Pharmacologic inhibition of MEK, a mitogen-activated protein kinase kinase upstream of ERK, integrally altered the signaling network and changed the temporal and spatial phenotypes in accordance with a priori model predictions. Our results demonstrate the dynamic, adaptive nature of in vivo signaling networks and identify natural, tissue-level variation in response phenotypes that can be deconvoluted only with quantitative, multi-variate computational modeling. To our knowledge, this is the first study to apply computational modeling of signaling networks to a bona fide in vivo system, and it lays a foundation for the use of systems-based approaches to understand how dysregulation of the cellular network state underlies complex disease.
登录
查看更多内容
影响因子：
32.4
作者：
Kontoyiannis, D;Pasparakis, M;Kollias, G
通讯作者：
Kollias, G
影响因子：
56.9
作者：
Lee, EG;Boone, DL;Ma, A
通讯作者：
Ma, A
影响因子：
11.4
作者：
Chen, CH;Wang, WJ;Chen, RH
通讯作者：
Chen, RH
影响因子：
5
作者：
Flaherty, Michael P.;Guo, Yiru;Tiwari, Sumit;Rezazadeh, Arash;Hunt, Greg;Sanganalmath, Santosh K.;Tang, Xian-Liang;Bolli, Roberto;Dawn, Buddhadeb
通讯作者：
Dawn, Buddhadeb
影响因子：
11.4
作者：
Eliopoulos, AG;Wang, CC;Tsichlis, PN
通讯作者：
Tsichlis, PN