Mathematical models of H. pylori gastric colonization

描述（由申请人提供）：幽门螺杆菌是一种螺旋形微需氧菌，持续定植于人胃，与上消化道疾病相关。越来越多的证据表明H.幽门螺杆菌个体被克隆变体的云定殖，类似于RNA病毒的准种。H. pylori多样化似乎对其体内持久性至关重要，越来越多的证据表明涉及多个位点的持续多样化。例如，涉及cagA和cagY的变异影响宿主组织相互作用。除了内源性点突变外，H. pylori基因组含有广泛的非随机分布的重复DNA，并且该生物体天然能够从其他H.幽门螺杆菌菌株;这些为多样化提供了重要机制;大量证据表明这发生在体内。该建议的假设是，H。幽门螺杆菌利用遗传变异作为适应（动态）宿主环境的主要机制。我们将研究重复DNA（目标1）和自然转化（目标2）之间的重组，以检查这些多样化方法的特点。这些研究将在体外进行，使用定量分析，探索所涉及的机制，并使用相关的H。pylori突变体，以检验提出的具体假设。我们将使用计算机模拟、实验和数学方法来表征这些机制，然后使用这些信息和方法来研究动物模型中的表型变异及其选择（目标3）。我们将继续关注H的选择。Leb转基因小鼠模型中幽门螺杆菌细胞表面刘易斯抗原变异。该实验系统的存在将允许分析导致基因型变化的遗传机制，产生改变的表型。实验结果将使确定性模型的发展与选择基因型和表型变异。

DESCRIPTION (provided by applicant): Helicobacter pylori are spiral, microaerophilic bacteria that persistently colonize the human stomach, and that are associated with diseases of the upper gastrointestinal tract. There is increasing evidence that H. pylori individuals are colonized by a cloud of clonal variants, analogous to the quasi-species of RNA viruses. The ability of H. pylori to diversify appears crucial to its in vivo persistence, with increasing evidence of ongoing diversification involving multiple loci. For example, variation involving cagA and cagY affect host tissue interactions. In addition to endogenous point mutations, the H. pylori genome contains extensive and non-randomly distributed repetitive DNA, and the organisms are naturally competent for uptake of DNA from other H. pylori strains; these provide important mechanisms for diversification; substantial evidence indicates that this occurs in vivo. The hypothesis of this proposal is that H. pylori uses genetic variation as a principal mechanism to adapt to (dynamic) host environments. We will study recombination between repetitive DNA (Aim 1) and natural transformation (Aim 2) to examine the characteristics of these diversification methods. These studies will be conducted in vitro using quantitative assays that explore the mechanisms involved, and using construction of relevant H. pylori mutants to test the specific hypotheses raised. We will use in silico, experimental, and mathematical approaches to characterize these mechanisms, and then use the information and approaches to study phenotypic variation and its selection in an animal model (Aim 3). We will continue to focus on the selection for H. pylori cell surface Lewis antigen variation in a Leb-transgenic mouse model. The existence of this experimental system will allow analysis of the genetic mechanisms leading to genotypic changes, producing altered phenotypes. The experimental results will enable development of deterministic models relating genotypic and phenotypic variation with selection.