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”是如何发挥其影响力的，人们还不太清楚。虽然一些毒素和病原体已经确定了环境应激的特定靶点，但我们认为环境应激的影响是通过靶分子参与的途径(S)和/或网络来调节的。此外，即使已经确定了环境压力和生物靶标之间的因果联系，必须先于治疗干预策略的生物学洞察力通常来得很慢。我们认为，环境压力的表型效应是通过基因产物和代谢物的动态网络的改变来调节的，而这种网络，无论是正常的还是扰动的，都表现出不能一次理解一个基因的紧急性质。我们的中心假设是，一个人必须了解复杂细胞网络的变化，才能充分了解基因、环境和表型之间的联系。Dana-Farber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“局部”地绘制由几个相互作用的分子组成的“分子电路”规模的细胞路径和网络，并在整个蛋白质组的规模上“全球”绘制细胞路径和网络的模型；这项工作已经产生了基本的生物学见解。我们建议使用模型系统作为广义环境压力的替代品，以开始了解细胞通路和网络是如何因环境侮辱而改变或修改的。我们选择了一个明确的、具有各种疾病后果的模型系统：病毒感染。在这里，我们探讨了这样一个概念，即以病毒为例的环境压力会影响网络的局部和全球特性，从而导致“疾病状态”。我们实现这些目标的计划概括为以下具体目标：1)描述一组具有相关生物学特性的病毒-宿主蛋白质-蛋白质的所有二元相互作用；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)将产生的相互作用和扰动数据与不同的基因组数据源集成，以得出动态细胞网络模型。

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.