Human Phenotyping

人类表型分析

• 批准号: 7638368
• 负责人: Samuel I Miller
• 金额: $ 28.42万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638368
• 关键词: Affect; Alleles; Antibiotics; Bacteria; Bacterial Infections; Biological Assay; Candidate Disease Gene; Categories; Causations; Cell Line; Cell Survival; Cell physiology; Cells; Cessation of life; Class; Communicable Diseases; Data; Data Analyses; Disease regression; European; Event; Family; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; HIV; Heritability; Human; Individual; Infection; Inflammatory; Knowledge; Malaria; Measures; Microbiology; Morbidity - disease rate; Mus; Organism; Parents; Pathogenesis; Phenotype; Plague; Population; Predisposition; Production; Proteins; Public Health; RNA Interference; Recording of previous events; Resistance; Salmonella; Salmonella typhi; Severities; Shapes; Today; Transgenic Organisms; Typhoid Fever; Universities; Variant; Washington; Yersinia; Yersinia pestis; base; cytokine; driving force; genetic variant; high throughput screening; macrophage; monocyte; mortality; pandemic disease; pathogen; pathogenic bacteria; uptake; vaccine development; volunteer

The idea that infectious disease acts as a major driving force in the variation and evolutionary history of humans is a compelling one that has been speculated on for the last half century. Despite this, few examples of association between human polymorphism and susceptibility to bacteria are known. Quantifying the amount of variation in bacterialsusceptibility is important for understanding the forces that have shaped our species and as a first step towards identifying the genes underlying the variation. Towards this end, 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 will provide a cellular picture of infection. Family-based association analysis will be used to correlate values from these assays with SNPs in candidate genes selected based on relevant cellular microbiology. Causation will be established by a combination of expression analysis, RNA interference, transgenic expression, and re-sequencing of candidate regions. Our long-term goal is to extend these studies to unbiased cell-based association screens. The knowledge of human variation to infection gained in this study is important for determining why some individuals are resistant to different infections and in developing therapies to decrease the mortality and morbidity of susceptible individuals. Such studies of bacterial pathogens have taken on an additional significance today, because of the threat of pathogenic bacteria being cultivated, modified, and used by terrorist groups.

传染病在变化和进化史上的主要动力的想法 人类是一个引人注目的人，在过去的半个世纪中被推测。尽管如此，很少有人 已知人类多态性和对细菌易感性之间的关联的例子。 量化细菌敏感性的变异量对于理解力量很重要 已经塑造了我们的物种，也是确定变异基因的第一步。向 这一目的，我们使用从 显然是正常人。细菌摄取，复制和定位的测定以及宿主细胞存活 细胞因子的产生将提供感染的细胞图片。基于家庭的协会分析将是 用于根据相关选择的候选基因中的SNP与SNP相关的值 细胞微生物学。通过表达分析，RNA的组合建立因果关系 候选区域的干扰，转基因表达和重新测序。我们的长期目标是 将这些研究扩展到公正的基于细胞的关联屏幕。对人类变异的了解 在这项研究中获得的感染对于确定为什么某些人对不同的不同 感染和开发疗法以降低易感人群的死亡率和发病率。 今天对细菌病原体的研究已经采取了额外的意义，因为 恐怖组织培养，修饰和使用致病细菌。