Rewiring Pathways and Networks by Environmental Perturbations

通过环境扰动重新布线路径和网络

基本信息

批准号：
7628431
负责人：
Marc Vidal
金额：
$ 55.72万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-10 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7628431
关键词：
Adenovirus E1A Proteins Adenoviruses Biological Biological Models Biology Cancer Center Cancerous Carcinogens Cell Cycle Regulation Cells Code Complex DNA Viruses Dana-Farber Cancer Institute Data Data Set Data Sources Development Disease Disease Association Disease Outcome Eating Environment Environmental Impact Exhibits Exposure to Genes Genome Genomics Genotype Goals Health Hepatitis B Virus Hepatitis C virus Human Human Papillomavirus Individual Infection Investigation Laboratories Lead Link Maps Mediating Modeling Modeling of Cellular Pathways Molecular Mutation National Institute of Environmental Health Sciences National Toxicology Program Oncogenic Viruses Organism Outcome Papillomavirus Parasites Pathway interactions Personal Satisfaction Phenotype Physiology Property Protein Family Protein-Protein Interaction Map Proteins Proteome RB1 gene Reporting Retinoblastoma Risk Role SV40 T Antigens Simian virus 40 Stress Structure Surface Systems Biology Testing Therapeutic Intervention Time Tissues Touch sensation Toxin Variant Viral Viral Proteins Virus Virus Diseases Virus Integration Work cancer type comparative disease phenotype fibrosarcoma genome-wide human DNA human disease insight melanoma molecular scale network models osteosarcoma pathogen protein protein interaction response stressor

项目摘要

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.

描述（由申请人提供）：人们普遍认为，环境压力（例如暴露于毒素或病原体）会对个人的健康和福祉产生深远的影响。这些“压力源”如何施加其影响不太了解。尽管已经确定了某些毒素和病原体的环境应力靶标，但我们建议环境应力的影响是通过目标分子参与的途径和/或网络介导的。此外，即使已经确定了环境压力与生物靶标之间的因果关系，也必须先于治疗干预策略之前的生物学见解。我们建议，环境应力的表型效应是通过基因产物和代谢产物的动态网络的变化而介导的，而这种正常和受扰的网络表现出了一个新兴的特性，这些特性一次是无法理解的一个基因。我们的中心假设是，必须了解复杂的细胞网络中的变化，以充分了解基因型，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），以及越来越多的实验室，正在以“分子回路”的规模“局部”绘制和建模细胞途径和网络。基本的生物学见解已经从这项工作中产生。我们建议将模型系统用作通用环境应力的替代物，以开始理解因环境损害而改变或修改细胞路径和网络的方式。我们选择了具有多种疾病结局的定义模型系统：病毒感染。在这里，我们探讨了一个概念，即病毒所用的环境压力影响网络的本地和全球性质，以诱导“疾病状态”。 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.