Systems biology approach to understanding host-pathogen interactions

理解宿主与病原体相互作用的系统生物学方法

• 批准号: 7652169
• 负责人: Malak Y.S. Kotb
• 金额: $ 22.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652169
• 关键词: Biological Markers; Biosensor; Candidate Disease Gene; Chromosome Mapping; Collaborations; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Event; Francisella tularensis; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Host Defense Mechanism; Host resistance; Immune; Immune response; Infection; Intervention; Knowledge; Link; Maps; Microsatellite Repeats; Molecular; Molecular Profiling; Mus; North Carolina; Parents; Pathogenesis; Pathway interactions; Pattern; Phenotype; Pilot Projects; Population; Predisposition; Purpose; Recombinants; Resistance; Severities; Severity of illness; System; Systems Biology; Testing; Translating; Triage; Universities; Virulent; abstracting; disease phenotype; genome sequencing; insight; novel therapeutics; pathogen; point of care; prognostic

Abstract Pilot Aims: Francisella tularensis is a highly virulent bacterial pathogen, and a prime candidate for use as a bioweapon. To develop effective countermeasures to F. tularensis, we need to have a clearer idea of molecular events controlling host-pathogen interactions. Our approach is to determine the genetics of host resistance and susceptiblilty to F. tularensis and then use the information to gain better insight into disease mechanism and molecular events controlling the interaction between this pathogen and the host. Our studies will reveal critical molecules involved in both pathogenesis used by pathogens and host defense mechanisms to which the pathogen is exceptionally sensitive. In this renewal proposal we will map the genetics of susceptibillity to the virulent F. tularensis Schu S4 strain. Our ultimate goal is to identify specific genes within the mapped QTLs that are responsible for differences in susceptibility or resistance and then parse these genes into networks of pathways that control the host response to the pathogen. To achieve our goal we will use a systems genetics approach that takes advantage of the advanced recombinant inbred BXD strains that were generated by advance recominbant intracrossing of two fully sequenced parent strains (DBA/2J and C57BL/6J). The genome sequence of the various genetically distinct BXD strains is known because the mice are heavily genotyped with SNP and microsatellite markers. It is therefore feasible to link infection phenotypes to the variable genotypes of this reference population of mice in order to map disease QTLs. This study will be done in collaboration with Dr. Tom Kawula at the University of North Carolina

抽象的 试点目的：弗朗西斯氏菌是一种高度毒性的细菌病原体，是用作生物武器的主要候选者。为了开发有效的对策，我们需要对控制宿主 - 病原体相互作用的分子事件有更清晰的想法。我们的方法是确定宿主抵抗力和对f菌的遗传学的遗传学，然后使用信息来更好地了解控制该病原体与宿主之间相互作用的疾病机制和分子事件。我们的研究将揭示病原体使用的发病机理和病原体非常敏感的宿主防御机制所涉及的关键分子。在此续签建议中，我们将将敏感性的遗传学映射到毒力的s骨shu s4菌株中。我们的最终目标是在映射的QTL中确定特定基因，这些基因是造成差异的原因 敏感性或抗性，然后将这些基因解析为控制宿主对病原体反应的途径网络。为了实现我们的目标，我们将使用一种系统遗传学方法，该方法利用了高级重组的近交BXD菌株，这些菌株是通过提前推荐的两种完全的折叠产生的 测序的父菌株（DBA/2J和C57BL/6J）。已知各种遗传学上不同BXD菌株的基因组序列，因为小鼠用SNP和微卫星标记大量基因分型。因此，将感染表型与该参考群体的可变基因型联系起来以绘制疾病QTL是可行的。这项研究将与大学的Tom Kawula博士合作完成 北卡罗来纳州