RESEARCH PROJECT 2

研究项目2

基本信息

批准号：
10224018
负责人：
JEFFERY S COX
金额：
$ 9.57万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-17 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224018
关键词：
Affect Bacterial Infections Behavior Biological Models CRISPR/Cas technology Cells Chlamydia trachomatis Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communicable Diseases Complex Coupled Critical Pathways Data Data Collection Disease Elements Gene Targeting Generations Genes Genetic Genetic Polymorphism Genetically Engineered Mouse Growth Human Human Biology Immune Immune response Individual Infection Inflammatory Inflammatory Response Innate Immune Response Innate Immune System Knock-out Knockout Mice Mammalian Genetics Modeling Mus Mycobacterium tuberculosis Nature Outcome Pathogenesis Pathway interactions Peripheral Blood Mononuclear Cell Phagocytes Phenotype Play Proteomics Research Research Project Grants Role Sampling Shapes Side Single Nucleotide Polymorphism Speed Staphylococcus aureus Study models Systems Biology Techniques Technology Testing Therapeutic Tissues Variant Work antimicrobial base clinically relevant functional genomics genetic technology genome editing human tissue in vivo innovation insight knock-down macrophage molecular dynamics mouse model mutant neutrophil novel pathogen pathogenic bacteria protein protein interaction response synergism therapeutic target

项目摘要

PROJECT 2: GENETIC IDENTIFICATION OF HOST INNATE PATHWAYS THAT CONTROL BACTERIAL PATHOGENESIS SUMMARY Phagocytes of the mammalian innate immune system, in particular macrophages and neutrophils, form the first line of defense upon bacterial infection and are armed with powerful mechanisms to limit bacterial growth and eradicate invaders. Bacterial pathogens, however, have evolved mechanisms to thwart these killing mechanisms of phagocytes, and to persist in human tissues. In addition to having direct antimicrobial activity, macrophages and neutrophils also initiate and shape powerful inflammatory responses that dramatically influence disease. Indeed, the inflammatory pathways elicited by each of the pathogens involved in this study - Mycobacterium tuberculosis (Mtb), Staphylococcus aureus (SA), and Chlamydia trachomatis (CT) - play major roles in bacterial persistence in tissues and in promoting disease. Pathogens must subvert these cells in order to grow and persist, but the host genes and cellular pathways that dictate the outcome of infection are not entirely clear. The broad idea of this proposal is to use unbiased, systematic approaches to probe the intimate interactions between pathogen and innate immune cells, and to use this information to make predictions about bacterial infectivity that will be tested in human samples in an iterative fashion to model host response during infection. We propose to systematically identify innate immune gene networks that underlie pathogenesis in clinically relevant model systems of infections with these three important bacterial pathogens. Using powerful CRISPR-based knockout strategies in both ex vivo infections and in mouse models, coupled with innovative approaches to identify functionally relevant polymorphisms in clinical samples, we seek to dramatically increase our understanding of infection biology of humans. We anticipate that these insights, coupled with the other elements of the HPMI Center, will point to novel vulnerabilities with therapeutic relevance.

项目2：遗传识别宿主先天途径控制细菌发病机理概括哺乳动物先天免疫系统的吞噬细胞，特别是巨噬细胞和中性粒细胞，形成了第一个细菌感染后的防御线，并具有强大的机制，以限制细菌的生长和根除入侵者。然而，细菌病原体已经发展了机制，以挫败这些杀戮吞噬细胞的机制，并持续在人体组织中。除了具有直接抗菌活性外，巨噬细胞和中性粒细胞也引发并塑造强大的炎症反应影响疾病。实际上，这项研究所涉及的每种病原体引起的炎症途径 - 结核分枝杆菌（MTB），金黄色葡萄球菌（SA）和沙眼衣原体（CT） - 发挥作用在细菌持久性组织和促进疾病中的作用。病原体必须按顺序颠覆这些细胞生长和持久，但是决定感染结果的宿主基因和细胞途径不是完全清楚。该提案的广泛思想是使用公正的，系统的方法来探究亲密病原体和先天免疫细胞之间的相互作用，并使用此信息来做出有关细菌感染性将在人类样品中以迭代方式进行测试，以模拟宿主反应。感染。我们建议系统地识别构成发病机理构成的先天免疫基因网络这三个重要的细菌病原体与临床相关的感染模型系统。使用功能强大在离体感染和鼠标模型中，基于CRISPR的淘汰策略，再加上创新的策略识别临床样本中与功能相关的多态性的方法，我们试图急剧提高我们对人类感染生物学的理解。我们预计这些见解，再加上 HPMI中心的其他元素将指出具有治疗意义的新型脆弱性。