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Modeling, analysis, and control of Syk-mediated signaling events for B cells and associated cellular response for B cells.

机译：建模，分析和控制Syk介导的B细胞信号转导事件以及相关的B细胞细胞反应。

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摘要

Understanding the immune system and its responses to foreign threats (antigens) is a matter of understanding the immune cells involved, their individual responses, and chemicals responsible for intracellular and intercellular communication. The overall immune response is driven by individual actions of neutrophils, antigen-presenting cells, and lymphocytes (T cells and B cells), among other cells. Intercellular communication is the means by which immune cells develop coordinated response while intracellular signals determine responses within a cell; both depend on systems of chemical reactions at their respective scales. The perspective taken in this dissertation is that of understanding B cells at the intracellular scale and the signaling molecules responsible for its responses.;B cells, a type of white blood cell in the immune system, identify antigens by binding to them via B cell receptors (BCRs). After identifying an antigen, mechanisms in the B cell membrane initiate a system of chemical interactions that propagate an intracellular signal and thereby determining the cell's response. In the first part of this thesis, we present a model for B cell signaling using dynamical systems and motivated by the desire to understand the role of the protein Syk. Syk is intricately involved in the early signaling events and is required for proper response to an antigen. The importance of this protein has led to mutant variants being genetically engineered to manipulate its impact. This mutant variant is one of the primary novelties of our model, and allows us to investigate the role of feedback loops involving Syk in producing responses. This mutant model is used to develop testable hypothesis regarding the B cell mutant kinase known as Syk-AQL.;It is often difficult to resolve questions regarding complicated biological systems through experimentation alone; this has led to the rise in the use of mathematical modeling in systems biology. Experimentation is still important, however, as data is needed to refine models, and designing experiments to most efficiently refine models is an important topic of research. This is a motivation for an interest in model-based experimental design, where experiments can be systematically chosen to reduce dynamic uncertainty in a given model. In the second part of this thesis, we provide background on methods of experiment design and discuss the Maximal Informative Next Experiment (MINE) method in greater detail. In particular, we provide a theoretical foundation for this method and prove a convergence result for MINE with nonlinear models. Design criteria have been developed to sequentially provide maximal reduction in uncertainty and one criterion has been rigorously justified. We will extend this analysis to other design criteria and in more general contexts. Experimental design results will be useful for work on B cell modeling as well as other applications. This project is a step towards better understanding cellular response and creating tools useful modeling biological systems.
机译：了解免疫系统及其对外来威胁（抗原）的反应是了解所涉及的免疫细胞，其个别反应以及负责细胞内和细胞间通讯的化学物质的问题。总体免疫应答是由嗜中性粒细胞，抗原呈递细胞和淋巴细胞（T细胞和B细胞）以及其他细胞的单独作用驱动的。细胞间通讯是指免疫细胞产生协调反应，而细胞内信号决定细胞内反应的方式。两者都取决于各自规模的化学反应系统。本文的观点是从细胞内的角度了解B细胞以及负责其反应的信号分子。B细胞是免疫系统中的一种白细胞，通过与B细胞受体结合来鉴定抗原（BCR）。鉴定抗原后，B细胞膜中的机制启动了化学相互作用的系统，该系统传播细胞内信号，从而确定细胞的反应。在本文的第一部分中，我们提出了一种使用动态系统的B细胞信号传导模型，其动机是希望了解蛋白质Syk的作用。 Syk复杂地参与了早期信号转导事件，并且是对抗原正确应答所必需的。这种蛋白质的重要​​性已导致对突变变体进行基因工程改造，以操纵其影响。此突变体变体是我们模型的主要新颖性之一，它使我们能够研究涉及Syk的反馈环在产生反应中的作用。该突变模型用于建立有关被称为Syk-AQL的B细胞突变激酶的可检验假说。通常仅通过实验就难以解决有关复杂生物系统的问题；这导致了系统生物学中数学建模的使用增加。但是，实验仍然很重要，因为需要数据来完善模型，而设计实验以最有效地完善模型是研究的重要课题。这是对基于模型的实验设计感兴趣的动机，在实验中可以系统地选择实验以减少给定模型中的动态不确定性。在本文的第二部分中，我们提供了实验设计方法的背景知识，并更详细地讨论了最大信息量下一个实验（MINE）方法。特别是，我们为该方法提供了理论基础，并证明了具有非线性模型的MINE的收敛结果。已经开发出设计标准以顺序地最大程度地减少不确定性，并且已经严格证明了一种标准。我们将在更一般的情况下将此分析扩展到其他设计标准。实验设计结果将对B细胞建模以及其他应用程序有用。该项目是朝着更好地了解细胞反应并创建有用的生物系统建模工具迈出的一步。

著录项

  • 作者

    McGee, Reginald L.;

  • 作者单位

    Purdue University.;

  • 授予单位 Purdue University.;
  • 学科 Mathematics.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 92 p.
  • 总页数 92
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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