Mathematical Models of H. Pylori gastric colonization

幽门螺杆菌胃定植的数学模型

基本信息

批准号：
8669633
负责人：
MARTIN J BLASER
金额：
$ 16.87万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-03-31
项目状态：
已结题

项目摘要

Bacteria are highly varied, and have developed mechanisms to diversify to enable survival in a dynamic world. Bacteria that are obligate colonizers of specific hosts have additional benefits and challenges compared with those with broader host ranges or those that are free-living. Helicobacter pylori is a gram negative bacterium that colonizes the human stomach. Once acquired, H. pylori persists in its host essentially for life (in the absence of antimicrobial therapy), is intimately related to human gastric tissues, including injection of H pylori constituents into epithelial cells, and when present, is the single dominant microbe in the human stomach. In addition to its major medical importance, H. pylori also is a model system for understanding microbial persistence in a host and the enabling mechanisms. Our hypothesis is that H. pylori evolved specific genetic mechanisms to create and control variation that maximizes its persistence in the gastric niche. We will address this hypothesis, through several Specific Aims: In Aim 1, we will assess how H. pylori controls intragenomic variation involving short sequence repeats (SSRs), using DNA repair and recombination genes. We plan to examine this question under steady state and fluctuating environments in vitro, and employ mathematical models to understand the underlying principles of the dynamics. In Aim 2, we will assess how H. pylori controls susceptibility to transforming DNA, and then determine its costs and benefits in vivo, in a murine model. Finally, in Aim 3, we plan to conduct experiments to understand the spatial localization (biogeography) of H. pylori colonization; to determine whether there is heterogeneity of sectoring of H. pylori strains in the gastric environment, under fixed or oscillating conditions. For each of the experiments to be performed, we will develop mathematical analyses to find the general properties under which the microbial populations diversify and are selected. Through such analyses, we hope to create the basis for a deeper understanding of how microbes are able to persist for long periods in their human hosts.

细菌种类繁多，并且已经发展出多样化机制，以便在动态世界中生存。与具有更广泛宿主范围或自由生活的细菌相比，作为特定宿主的专性定殖者的细菌具有额外的好处和挑战。幽门螺杆菌是一种定植于人类胃中的革兰氏阴性细菌。一旦获得，幽门螺杆菌基本上会在其宿主体内终生存在（在没有抗菌治疗的情况下），与人类胃组织密切相关，包括将幽门螺杆菌成分注射到上皮细胞中，并且当存在时，它是胃组织中的单一优势微生物。人的胃。除了其重要的医学重要性外，幽门螺杆菌还是了解宿主体内微生物持久性及其促进机制的模型系统。我们的假设是，幽门螺杆菌进化出特定的遗传机制来创造和控制变异，从而最大限度地提高其在胃生态位中的持久性。我们将通过几个具体目标来解决这一假设：在目标 1 中，我们将评估幽门螺杆菌如何使用 DNA 修复和重组基因来控制涉及短序列重复 (SSR) 的基因组内变异。我们计划在体外稳态和波动环境下研究这个问题，并利用数学模型来理解动力学的基本原理。在目标 2 中，我们将评估幽门螺杆菌如何控制 DNA 转化的易感性，然后在小鼠模型中确定其体内成本和收益。最后，在目标 3 中，我们计划进行实验来了解幽门螺杆菌定植的空间定位（生物地理学）；确定在固定或振荡条件下胃环境中幽门螺杆菌菌株的分区是否存在异质性。对于要进行的每个实验，我们将进行数学分析，以找到微生物种群多样化和选择的一般特性。通过这样的分析，我们希望为更深入地了解微生物如何能够在人类宿主体内长期存在奠定基础。