Rewiring Pathways and Networks by Environmental Perturbations

描述（由申请人提供）： 人们普遍认识到，环境压力，如接触毒素或病原体，可能对个人健康和福祉产生深远影响。这些“压力源”如何发挥其影响力还不太清楚。虽然已经确定了一些毒素和病原体的环境压力的具体目标，我们提出环境压力的影响是通过靶分子参与的途径和/或网络介导的。此外，即使已经确定了环境压力与生物靶点之间的因果关系，在治疗干预策略之前必须进行的生物学洞察通常也进展缓慢。我们认为，环境压力的表型效应介导的基因产物和代谢物的动态网络中的改变，这样的网络，正常和扰动，表现出新兴的属性，不能理解一个基因的时间。我们的中心假设是，必须了解复杂的细胞网络的变化，以充分了解基因型，环境和表型之间的联系。丹娜-法伯癌症研究所的癌症系统生物学中心（CCSB）与越来越多的实验室一起，正在绘制和建模细胞通路和网络，既在“局部”由几个相互作用的分子组成的“分子电路”的规模上，又在整个蛋白质组的规模上“全球”;基本的生物学见解已经从这一工作中出现。我们建议使用一个模型系统作为广义环境应力的替代品，开始理解细胞通路和网络如何因环境损伤而改变或修改。我们选择了一个定义的模型系统，具有各种疾病结果：病毒感染。在这里，我们探讨的概念，环境压力，例如病毒，影响网络的局部和全局属性，以诱导“疾病状态”。我们实现这些目标的计划总结在以下具体目标中：1）描述一组具有相关生物学特性的病毒的所有二元病毒-宿主蛋白质-蛋白质相互作用2）系统地测试每种病毒蛋白质破坏或改变宿主-宿主蛋白质相互作用的能力，3）将所得的相互作用和扰动数据与不同的基因组数据源整合以获得动态细胞网络模型。

DESCRIPTION (provided by applicant): It is widely appreciated that environmental stresses, such as exposure to toxins or pathogens, can have profound impact on individual health and well-being. How these "stressors" exert their influence is less well understood. While specific targets of environmental stresses have been identified for some toxins and pathogens, we propose that the impact of environmental stresses is mediated through the pathway(s) and/or networks in which the target molecule participates. Furthermore, even where a causal association between an environmental stress and a biological target has been identified, the biological insight that must precede a strategy for therapeutic intervention has generally been slow in coming. We suggest that the phenotypic effects of environmental stresses are mediated by alterations in a dynamic network of gene products and metabolites, and such networks, normal and perturbed, exhibit emergent properties that cannot be understood one gene at a time. Our central hypothesis is that one must understand changes in complex cellular networks to fully understand the link between genotype, environment, and phenotype. The Center for Cancer Systems Biology (CCSB) at the Dana-Farber Cancer Institute, together with a growing number of laboratories, is mapping and modeling cellular pathways and networks both "locally" at the scale of "molecular circuits" made of a few interacting molecules, and "globally" at the scale of the whole proteome; fundamental biological insights have already emerged from this body of work. We propose to use a model system as a surrogate for generalized environmental stresses to begin understanding how cellular pathways and networks are altered or modified as a consequence of environmental insult. We have chosen a defined, model system with a variety of disease outcomes: viral infection. Here we explore the concept that environmental stresses, as exemplified by viruses, influence local and global properties of networks to induce "disease states". Our plans to achieve these goals are summarized in the following specific aims: 1) Profile all binary viral-host protein-protein interactions for a group of viruses with related biological properties 2) Systematically test each viral protein for its ability to disrupt or alter host-host protein interactions, 3) Integrate the resulting interaction and perturbation data with diverse genomic data sources to derive dynamic cellular network models.