RESEARCH PROJECT 2

研究项目2

• 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
• 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

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：宿主先天途径的遗传鉴定， 控制细菌致病 总结 哺乳动物先天免疫系统的吞噬细胞，特别是巨噬细胞和嗜中性粒细胞，形成第一免疫系统。 细菌感染后的防线，并配备了强大的机制，以限制细菌的生长， 消灭入侵者。然而，细菌病原体已经进化出了阻止这些杀戮的机制 吞噬细胞的机制，并坚持在人体组织。除了具有直接的抗微生物活性外， 巨噬细胞和嗜中性粒细胞也启动和形成强大的炎症反应， 影响疾病。事实上，本研究中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）-主要 在细菌在组织中的持久存在和促进疾病中的作用。病原体必须破坏这些细胞， 但决定感染结果的宿主基因和细胞途径却没有 完全清楚这个建议的主要思想是使用公正的，系统的方法来探测亲密的 病原体和先天免疫细胞之间的相互作用，并利用这些信息来预测 将在人体样本中以迭代方式测试细菌感染性，以模拟 感染我们建议系统地识别先天免疫基因网络，这些基因网络是先天免疫性心脏病发病机制的基础。 这三种重要细菌病原体感染的临床相关模型系统。使用强大 在离体感染和小鼠模型中基于CRISPR的敲除策略，加上创新的 为了鉴定临床样品中功能相关的多态性，我们试图显著地 增加我们对人类感染生物学的了解。我们预计，这些见解，加上 HPMI中心的其他元素，将指出新的弱点与治疗相关性。