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

描述（由申请人提供）：所有活细胞都能够从其微环境中提取信息，并对各种相关挑战做出适当的反应。潜在的信号转导网络可能相当复杂，需要将复杂的计算模型和精确的实验相结合。不幸的是，目前对细胞信号传导的计算和实验分析经常存在这样的缺陷，如从周围的信号网络中分离出一条途径，忽视信号输出中的细胞-细胞变异性，或者在原生组织中研究细胞-细胞通信所提供的背景之外的信号传导。本更新提案旨在通过开发新的方法和工具，为解决这些研究局限性提供一个框架，并提出一个更现实的肿瘤坏死因子（TNF）趋化因子信号响应的综合分析的详细计划。我们的分析将特别强调对信号通路的信息传递特性及其在定义表型结果精度方面的作用的理解，包括基因表达的调节。分析结果将为研究单细胞和群体反应之间的关系提供一个新的平台，并推动基于信息理论的对细胞内信号处理和细胞通信的理解的发展。我们预计，对信号串音的复杂性、对相同刺激的细胞反应多样性的调控以及细胞间通讯的细微差别的定量理解，将有助于建立一个更现实的框架，以理解人类疾病，包括免疫系统的功能，以及旨在调节NF-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. PUBLIC HEALTH RELEVANCE: Cells respond to their external environment by extracting information out of chemical signals they receive from other cells. This leads to changes in protein activity and gene expression, ultimately deciding the function and fate of the cell. These responses are complicated by differences between individual cells as well as communication between cells. Understanding the responses may benefit from analyses that combine experiment and mathematical modeling. In this context, we propose to study in detail two signals induced by inflammation in mammalian cells. Through such analyses we anticipate to uncover novel principles and mechanisms by which cells respond to external stimuli.