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，需要将复杂的计算建模和精确的实验相结合。不幸的是，目前的细胞信号传导的计算和实验分析经常遭受这样的陷阱，如从周围的信号网络的途径的隔离，忽视信号输出的细胞-细胞的变异性或研究信号提供的背景下，在天然组织中的细胞-细胞通信。该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，并提出一个更现实的综合分析响应于趋化因子肿瘤坏死因子（TNF）的信号转导的详细计划。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（包括基因表达调控）的精确性方面的作用的理解。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，并推动基于信息论的细胞内信号处理和细胞通讯理解的发展。我们预计，对信号串扰的复杂性、对相同刺激的细胞反应的多样性的调节以及细胞间通信的细微差别的定量理解，将有助于开发一个更现实的框架，用于理解人类疾病，包括免疫系统的功能，以及旨在调节NF-κ B和JNK信号的药物开发。 公共卫生相关性：细胞通过从其他细胞接收的化学信号中提取信息来响应外部环境。这导致蛋白质活性和基因表达的变化，最终决定细胞的功能和命运。这些反应由于单个细胞之间的差异以及细胞之间的通信而变得复杂。理解响应可能受益于结合联合收割机实验和数学建模的分析。在这种情况下，我们建议详细研究哺乳动物细胞中炎症诱导的两个信号。通过这样的分析，我们期望揭示细胞对外部刺激做出反应的新原理和机制。

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.