Modeling the Flagella Regulon in Salmonella

描述(申请人提供)：这是一个细菌遗传学家、数学生物学家和数学家之间的合作项目，将使用数学模型来研究导致鞭毛有序组装的遗传网络。为了量化负责鞭毛构建的调控分子，我们将建立一个微分方程组来解释在鼠伤寒沙门氏菌中诱导鞭毛调节子后结构蛋白和调控蛋白出现的动力学。最初的模型将由大约18个关键蛋白质和操纵子的方程式组成，这些蛋白质和操纵子控制细菌鞭毛的有序组装。然后，我们将使用定量Western-Blot分析、操纵子和基因融合、微阵列、显微镜和细菌运动性分析来估计参数值，测试模型的假设，并调查最初的鞭毛生物合成模型中没有包含的其他基因。这些数据将被用来创建改进的模型，这些模型可以用来研究遗传反馈和时间延迟在创建循环模式中的作用。这些精细的模型也可以被操纵，以预测如果这些操纵子以不同的方式进化会发生什么。例如，我们可以从理论上测试，如果一些3类基因处于2类启动子的控制之下，人们会期待什么。然后，这些理论预测将在实验室中使用基因操纵的菌株进行验证。由于TTSS是抗体的潜在靶点，对这些调节分子的定量研究可能有助于此类疫苗的开发。这是一个易于操作的系统，其中的结构可以很容易地可视化。因此，我们认为鞭毛可以作为复杂调控系统的模型系统。

DESCRIPTION (provided by applicant): This is a collaborative project between a bacterial geneticist, a mathematical biologist and a mathematician that will use mathematical models to study the genetic networks responsible for the ordered assembly of the flagellum. To quantify the regulatory molecules responsible for the construction of the flagella, we will develop a system of differential equations to explain the kinetics of appearance of structural and regulatory proteins following induction of flagella regulon in S. typhimurium. The initial model will consist of a equations for approximately 18 key proteins and operons that govern the ordered assembly of bacterial flagella. We will then use quantitative Western-blot analysis, operon and gene fusions, micro-arrays, microscopy, and bacterial motility assays to estimate parameter values, test the assumptions of the model, and investigate other genes not incorporated in the initial model for flagella biosynthesis. This data will be used to create refined models that can be used to study the role of genetic feedbacks and time-delays in creating cyclic patterns. These refined models can also be manipulated to predict what would happen had these operons evolved differentially. For example, we could test theoretically what one would expect if some of some of the class 3 genes were under the control of a class 2 promoter. These theoretical predictions will then be tested in the laboratory using genetically manipulated strains. Because TTSS is a potential target for antibodies, a quantitative study of these regulatory molecules could aid in the development of such vaccines. This is an easy-to-manipulate system in which structures can be easily visualized. Thus, we propose that the flagella could serve a model system for complex regulatory systems.