Comparative analysis of information transfer in NF-kapppaB and MAPK pathways

描述(申请人提供)：所有活细胞都能够从它们的微环境中提取信息，并对各种相关的挑战做出适当的反应。潜在的信号转导网络可能非常复杂，需要将复杂的计算模型和精确的实验结合在一起。遗憾的是，当前对细胞信号的计算和实验分析经常遇到这样的缺陷，如将一条通路与周围的信号网络隔离，忽视信号输出中细胞-细胞的可变性，或者脱离天然组织中细胞-细胞通讯提供的背景来研究信号。这项更新提案旨在通过开发新的方法和工具来提供解决这些研究局限性的框架，并提出更现实的信号综合分析的详细计划，以响应一种趋化因子--肿瘤坏死因子(TNF)。我们分析的重点将是了解信号通路的信息传递特性及其在定义表型结果的精确度方面的作用，包括对基因表达的调节。分析结果将为研究单个细胞和群体反应之间的关系提供一个新的平台，并推动基于信息论的理解细胞内信号处理和细胞通信的发展。我们预计，定量了解信号串扰的复杂性，调节细胞对相同刺激的反应的多样性，以及细胞间通信的细微差别，将有助于开发更现实的框架来理解人类疾病，包括免疫系统的功能，以及旨在调节核因子-kappaB和JNK信号的药物开发。

DESCRIPTION (provided by applicant): All living cells are capable of extracting information from their micro-environment and mounting appropriate responses to a variety of associated challenges. The underlying signal transduction networks can be quite complex, necessitating for their unraveling a combination of sophisticated computational modeling and precise experimentation. Unfortunately, current computational and experimental analysis of cell signaling frequently suffers from such pitfalls as isolation of a pathway from surrounding signaling network, disregard of the cell-cell variability in the signaling outputs or studying signaling out of the context provided of by cell-cell communication in the native tissues. This renewal proposal is aimed at providing a framework for addressing these research limitations through development of novel methods and tools, and putting forward a detailed plan of a more realistic integrative analysis of signaling in response to a chemokine, tumor necrosis factor (TNF). A particular emphasis of our analysis will be on understanding of the information transfer properties of signaling pathways and its role in defining the precision of the phenotypic outcomes, including regulation of gene expression. The results of the analysis will provide a new platform for investigation of the relationship between the single cell and population responses and drive the development of the information theory based understanding of intracellular signal processing and cell communication. We anticipate that the quantitative understanding of the complexity of signaling cross-talk, regulation of diversity of cell responses to the same stimulus and nuances of cell-cell communication will facilitate development of a more realistic framework for understanding of the human disease, including functioning of the immune system, and drug development aimed at regulation of the NF-kappaB and JNK signaling.