The dynamics of granuloma formation in tuberculosis

描述(由申请人提供) 这项建议的目的是解释肉芽肿的形成。 感染结核分枝杆菌。了解肉芽肿的形成 和功能将阐明控制的主要免疫机制 肺结核感染。我们的目标是模拟肉芽肿的过程 在时空尺度上形成，并以时间推移的形式呈现结果 电影格式。这将产生一个交互工具来研究 肉芽肿形成和功能中的特异性免疫元件。发展中的 一个虚拟的人类感染模型将允许整合过多的 趋化因子、细胞因子、细胞内流信息和其他相关信息 免疫因素由实验系统产生的免疫因素为此， 强大的技术(例如，微阵列)可用于获得 全面的基因表达数据。使用这些方法来调查表情 非人类灵长类动物和老鼠的肉芽肿内将使我们能够 确定哪些免疫介质参与肉芽肿的形成， 它们在队形中的表达时间是什么，它们的位置是什么 在肉芽肿内。进一步的研究将指明哪些细胞类型是 表达了哪些调解人。我们的具体目标是：(1)确定 参与的宿主免疫元件的时空表达 利用基因表达工具形成肉芽肿小鼠模型 结核病(2)识别宿主免疫的时间和空间表达 使用基因表达工具研究参与肉芽肿形成的因素 小鼠结核病模型(3)确定肉芽肿的动力学 用肉芽肿数学模型研究人类肉芽肿的形成和功能 对结核病的反应。通过这种独特的方法， 控制肉芽肿形成的多种因素将被定义。 将确定管理这些互动的关键参数。一种能力 在模型中合成实验产生的数据允许 对肉芽肿形成的动力学的理解不仅仅是总和 它的各个部分。

DESCRIPTION (provided by applicant) The goal of this proposal is to explain the formation of granuloma in infection with Mycobacterium tuberculosis. Understanding granuloma formation and function will elucidate the primary immune mechanism for controlling tuberculosis infection. Our goal is to simulate the process of granuloma formation on a spatio-temporal scale and present the results in a time-lapse movie format. This will yield an interactive tool to study the role of specific immune elements in granuloma formation and function. Development of a virtual model of human infection will allow for integration of the plethora of chemokine, cytokine, cellular influx information and other relevant immunological factors, as generated by experimental systems. To this end, powerful techniques (e.g., microarrays) are available for obtaining comprehensive gene expression data. Using these methods to survey expression within the granulomas of non-human primates and mice will enable us to determine which immunological mediators are involved in granuloma formation, what the timing of their expression is in the formation, and their location within the granuloma. Further studies will indicate which cell-types are expressing which mediators. Our specific aims are to: (1) Identify the temporal and spatial expression of host immune elements participating in granuloma formation using gene expression tools in murine models of tuberculosis (2) Identify the temporal and spatial expression of host immune elements participating in granuloma formation using gene expression tools in murine models of tuberculosis (3) Determine the dynamics of granuloma formation and function in humans using mathematical models of the granuloma response in tuberculosis. Through this unique approach, the interaction of multiple factors that control the formation of the granuloma will be defined. Key parameters governing these interactions will be identified. The ability to synthesize the data generated by the experiments in the models allows for an understanding of the dynamics of granuloma formation as more than the sum of its parts.