Mathematical Models of H. Pylori gastric colonization

幽门螺杆菌胃定植的数学模型

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8669633
• 关键词: Address; Affect; Africa; Bacteria; Biological; Biological Models; Cells; Costs and Benefits; DNA; DNA Repair; Disease; Environment; Epithelial; Epithelial Cells; Equilibrium; Evolution; Gastric Tissue; Genes; Genetic; Genetic Recombination; Genetic Variation; Genomics; Gram-Negative Bacteria; Health; Helicobacter pylori; Heterogeneity; Human; Human body; In Vitro; Injection of therapeutic agent; Life; Medical; Microbe; Modeling; Mus; Mutation; Population; Predisposition; Primates; Property; Recording of previous events; Short Tandem Repeat; Stomach; Structure; Systems Biology; Tissues; Ulcer; Variant; Virulence; Work; antimicrobial; base; cost; in vivo; interest; malignant stomach neoplasm; mathematical model; microbial; migration; research study; Address; Affect; Africa; Bacteria; Biological; Biological Models; Cells; Costs and Benefits; DNA; DNA Repair; Disease; Environment; Epithelial; Epithelial Cells; Equilibrium; Evolution; Gastric Tissue; Genes; Genetic; Genetic Recombination; Genetic Variation; Genomics; Gram-Negative Bacteria; Health; Helicobacter pylori; Heterogeneity; Human; Human body; In Vitro; Injection of therapeutic agent; Life; Medical; Microbe; Modeling; Mus; Mutation; Population; Predisposition; Primates; Property; Recording of previous events; Short Tandem Repeat; Stomach; Structure; Systems Biology; Tissues; Ulcer; Variant; Virulence; Work; antimicrobial; base; cost; in vivo; interest; malignant stomach neoplasm; mathematical model; microbial; migration; research study

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.

细菌高度多样，并且已经开发出多样化的机制，以使能够在动态世界中生存。与宿主范围更广泛或自由生活的细菌相比，特定宿主的卑鄙殖民者的细菌具有额外的好处和挑战。幽门螺杆菌是一种革兰氏阴性细菌，可在人类的胃中定位。一旦获得，幽门螺杆菌在其宿主中基本上​​一直存在于生命中（在没有抗菌治疗的情况下），与人类胃组织密切相关，包括将幽门螺杆菌组成注射到上皮细胞中，而当存在的是人类胃中的单个主要微生物。除了其主要的医学重要性外，幽门螺杆菌还是理解宿主和启用机制中微生物持久性的模型系统。我们的假设是，幽门螺杆菌发展了特定的遗传机制，以创造和控制其在胃生态位的持久性最大化。我们将通过几个特定目的解决这一假设：在AIM 1中，我们将使用DNA修复和重组基因评估幽门螺杆菌如何控制涉及短序列重复序列（SSR）的基因组变异。我们计划在稳态和体外波动的环境下检查这个问题，并采用数学模型来了解动力学的基本原理。在AIM 2中，我们将评估幽门螺杆菌如何控制转化DNA的敏感性，然后在鼠模型中确定其体内的成本和收益。最后，在AIM 3中，我们计划进行实验，以了解幽门螺杆菌定植的空间定位（生物地理）。确定在固定或振荡条件下，胃环境中幽门螺杆菌菌株的座位的异质性。为了进行每个实验，我们将开发数学分析，以找到微生物种群多样化并选择的一般特性。通过这样的分析，我们希望为对微生物如何在人类寄主中长期持续存在更深入地了解基础。