Functional genomics for Chlamydia

衣原体功能基因组学

基本信息

批准号：
10464275
负责人：
P Scott Hefty
金额：
$ 81.08万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10464275
关键词：
Achievement Acute Address Alleles Area Bacteria Biological Biological Models Biology Cells Characteristics Chimera organism Chlamydia Chlamydia Infections Chlamydia muridarum Chlamydia trachomatis Complex Defect Development Essential Genes Female Female genitalia Foundations Generations Genes Genetic Genetic Determinism Genetic study Genome Goals Growth Growth and Development function Horizontal Gene Transfer Human Hybrids In Vitro Infection Influentials Interferon Type II Investigation Knowledge Lead Libraries Maps Mediating Medical History Membrane Membrane Proteins Modeling Modernization Molecular Mus Mutagenesis Natural History Nature Organism Outcome Pathogenesis Pathology Pathway interactions Phase Phenotype Play Prevention strategy Proteins Reproductive Health Research Personnel Role Series Sexually Transmitted Diseases Shapes System Technology Technology Transfer Tropism Ubiquitin Virulence Virulence Factors Work acute infection clinically relevant cohort design experience experimental study functional genomics gene product genetic manipulation genome-wide human pathogen in vitro Assay in vivo innovation interest microorganism mouse model mutant novel therapeutics pathogen pathogenic bacteria pressure protein function reproductive reproductive tract tool

项目摘要

PROJECT SUMMARY For bacterial pathogens, the first studies that begin to define the microorganism’s functional genetic nature on a genome-wide scale, frequently represent a landmark and highly impactful achievement. The major human pathogen Chlamydia trachomatis is a bacterium for which such studies have not been performed, in large part due to Chlamydia’s obligate intracellular nature and historical intractability to modern genetic manipulation. With the development of two major genetic tools for Chlamydia by our group—transposon mutagenesis and lateral gene transfer chimeras—functional genomic investigations in Chlamydia are now possible. Our long term goal is to globally define and functionally characterize the genetic correlates to C. trachomatis infection and pathogenesis. Using the complementary approaches of transposon mutagenesis and interspecies chimeras, we propose to: (i) identify the major genetic determinants of Chlamydia infection using a clinically relevant mouse model and in vitro assays; (ii) determine the Chlamydia genes associated with host adaptation by exploiting interspecies lateral gene transfer within Chlamydia and the signature host tropisms of the parental strains; (iii) characterize the mechanisms of host cell subversion by the secreted inclusion membrane effector proteins IncU and IncS. These efforts are essential for gaining a functional appreciation of the role that unique chlamydial genes play in the organism’s growth and development, and also Chlamydia’s evolutionary adaptation to successfully maintain infection and pathogenesis in complex mammalian hosts. We anticipate that Chlamydia will serve as a model obligate intracellular bacterium, and, therefore, the knowledge obtained from this work will broadly extend to other pathogens that have evolved an obligate intracellular niche in their mammalian hosts. Identification of these loci is critical for our understanding of the mechanisms through which Chlamydia have adapted to mammalian hosts, and represents an important step towards elucidating the major virulence correlates of C. trachomatis in humans.

项目摘要对于细菌病原体，首先开始定义微生物的功能性遗传性质的研究全基因组量表，通常代表着具有里程碑意义和高度影响力的成就。主要人物病原体衣原体沙眼是一种细菌，在很大程度上没有进行此类研究由于衣原体的细胞内性质和对现代遗传操纵的历史性顽固性。随着我们小组为衣原体开发两种主要的遗传工具：Transposon诱变和现在可以进行侧基因转移嵌合体 - 衣原体的功能基因组研究。我们的长期目标是在全球定义并在功能上表征遗传与沙眼藻的相关性感染和发病机理。使用转座子诱变的完整方法和种间嵌合体，我们建议：（i）使用A的主要遗传决定剂临床相关的小鼠模型和体外测定；（ii）确定与宿主相关的衣原体基因通过利用种间间基因转移在衣原体内的横向基因转移和签名宿主的托管宿主向上的适应父母的压力；（iii）表征通过分泌包含的宿主细胞颠覆的机制膜效应蛋白Incu and Incs。这些努力对于获得独特的衣原体基因在功能中起作用的作用至关重要生物体的生长和发育，以及衣原体的进化改编维持复杂哺乳动物宿主的感染和发病机理。我们预计衣原体将作为一个模型，具有细胞内细菌的义务，因此，从这项工作中获得的知识将广泛延伸到其他病原体，这些病原体在其哺乳动物宿主中进化了强制性细胞内生态位。这些基因座的识别对于我们对衣原体所具有的机制的理解至关重要适应哺乳动物宿主，代表了阐明主要病毒的重要一步人类中的沙眼梭状疱疹的相关性。