Diversity of Host Pathogen Interactions

宿主病原体相互作用的多样性

基本信息

批准号：
8236991
负责人：
Samuel I Miller
金额：
$ 39.16万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8236991
关键词：
Affect Alleles Animal Model Antibiotics Bacteria Bacterial Infections Biological Assay Burkholderia Candidate Disease Gene Categories Cell Death Cell Survival Cell physiology Cells Centers of Research Excellence Cessation of life Chronic Communicable Diseases Computer Simulation Databases Disease Emerging Communicable Diseases Epidemiology Etiology European Exhibits Family Francisella Funding Genes Genetic Genetic Polymorphism Genotype Goals HIV Health Heritability Human In Vitro Individual Infection Inflammatory Inflammatory Bowel Diseases Internet Knock-out Knowledge Life Style Location Malaria Measurement Measures Messenger RNA Methods Microbiology Morbidity - disease rate Mus Mutation Natural Immunity Nature Parents Pathogenesis Phenotype Population Predisposition Production Proteins Public Health RNA Interference RNA Splicing Recording of previous events Reproducibility Resistance Rheumatoid Arthritis Salmonella Series Severities Signal Pathway System Testing Transgenic Mice Validation Variant Virulence Whole Organism Work Yersinia base biodefense biosecurity case control clinical phenotype comparative cytokine fitness genome wide association study genome-wide human disease interest knock-down lymphoblastoid cell line monocyte mortality offspring overexpression pandemic disease pathogen pathogenic bacteria research clinical testing research study response therapy development uptake vaccine development

项目摘要

Despite improvements in public health, advancements in vaccines, and the development of many classes of antibiotics, infectious disease is still responsible for over a quarter of all deaths worldwide. However, even for the most devastating of pandemics, history demonstrates a large variability in the severity and duration of infection. Despite this, few examples of association between human polymorphism and susceptibility to bacteria are known. The goals of this project are to 1) identify aspects of bacterial infection in humans that exhibit heritable variation, 2) determine the genetic changes that are responsible, and 3) assess the relevance of this variation on the fitness of whole organisms. We are measuring intermediate phenotypes of susceptibility using cells derived from populations of apparently normal individuals. Assays of bacterial uptake, replication, and localization, and host-cell survival and cytokine production provide a quantitative, cellular picture of infection. Family-based association analyses are being used to correlate values from these assays with SNPs in candidate genes selected based on relevant cellular microbiology and on a genome-wide scale. Causation of the identified SNPs is being established by a combination of expression analysis, RNA interference, and overexpression experiments. Finally, relevance to health and disease will be measured using association analysis of clinical phenotypes and phenotypic measurements of transgenic mice.

尽管公共卫生有所改善，疫苗进展以及许多类别的发展抗生素，传染病仍负责全球所有死亡的四分之一。但是，甚至对于最毁灭性的大流行，历史表明了严重性和持续时间的差异很大感染。尽管如此，人类多态性与易感性之间的关联例子很少细菌是已知的。该项目的目标是1）确定表现可遗传的人类细菌感染的各个方面变异，2）确定负责的遗传变化，3）评估这一点的相关性整个生物体适应性的变化。我们正在测量易感性的中间表型使用源自明显正常个体种群的细胞。细菌摄取，复制的测定和本地化以及宿主细胞的生存和细胞因子的产生提供了定量的细胞图片感染。基于家庭的关联分析用于将这些测定的值与基于相关细胞微生物学和全基因组量表选择的候选基因中的SNP。通过表达分析的组合建立了鉴定的SNP的因果关系干扰和过表达实验。最后，将测量与健康和疾病的相关性利用转基因小鼠的临床表型和表型测量的结合分析。