Fault Diagnosis Engineering of Digital Circuits Can Identify Vulnerable Molecules in Complex Cellular Pathways
Fault Diagnosis Engineering of Digital Circuits Can Identify Vulnerable Molecules in Complex Cellular Pathways
复制标题
DOI：
10.1126/scisignal.2000008
复制
发表时间：
2008-10-21
影响因子：
7.3
通讯作者：
Emamian, Effat S.
中科院分区：
文献类型：
--
作者：
Abdi, Ali;Tahoori, Mehdi Baradaran;Emamian, Effat S.
复杂系统工程方法在细胞信号网络中的应用将导致对复杂疾病的新的理解和新的治疗方法。在电路故障诊断工程领域，有各种方法来识别复杂数字电子电路中的缺陷或易损元件。然而，在生物系统中，关于相互连接的信号通路对每个特定分子功能障碍的脆弱性的知识是有限的。通过开发适当的生物驱动的数字脆弱性评估方法，可以确定复杂信号网络对每个分子可能功能障碍的脆弱性。为了显示这种方法的实用性，我们分析了三个特征良好的信号网络-一个调节caspase 3活性的细胞网络，一个调节p53活性的网络，以及一个调节转录因子CREB（腺苷3 '，5'-单磷酸反应元件结合蛋白）活性的中枢神经系统网络。我们发现不同分子的脆弱性值之间的重要差异。大多数已鉴定的高度脆弱分子在功能上是相关的，并且是这些网络的已知关键调节器。实验数据证实了数字脆弱性评估能够正确预测CREB网络中的关键监管机构。因为这种方法可以提供对导致人类疾病的关键分子的洞察，它可以帮助确定药物开发的关键目标。
The application of complex system engineering approaches to cell signaling networks should lead to novel understandings and, subsequently, new treatments for complex disorders. In the area of circuit fault diagnosis engineering, there are various methods to identify the defective or vulnerable components of complex digital electronic circuits. In biological systems, however, knowledge is limited regarding the vulnerability of interconnected signaling pathways to the dysfunction of each specific molecule. By developing proper biologically driven digital vulnerability assessment methods, the vulnerability of complex signaling networks to the possible dysfunction of each molecule can be determined. To show the utility of this approach, we analyzed three well-characterized signaling networks-a cellular network that regulates the activity of caspase3, a network that regulates the activity of p53, and a central nervous system network that regulates the activity of the transcription factor CREB ( adenosine 3', 5'-monophosphate response element-binding protein). We found important differences among the vulnerability values of different molecules. Most of the identified highly vulnerable molecules are functionally related and known key regulators of these networks. Experimental data confirmed the ability of digital vulnerability assessment to correctly predict key regulators in the CREB network. Because this approach may provide insight into key molecules that contribute to human diseases, it may aid in the identification of critical targets for drug development.