Role of CED-1 in the Systemic Response to Pathogen Infection in C. elegans

CED-1 在秀丽隐杆线虫病原体感染的系统反应中的作用

• 批准号: 8457855
• 负责人: Brian Head
• 金额: $ 5.22万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457855
• 关键词: Address; American Society of Hematology; Animal Model; Animals; Autoimmune Diseases; Bacteria; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cells; Cherry - dietary; Chronic; Communication; Communities; Coupled; Data; Disease; Endocrine; Family; G-Protein-Coupled Receptors; Gene Expression; Genes; Genome; Growth; Head; Health; Homologous Gene; Human; Immune; Immune response; Immune system; Immunity; Infection; Inflammatory; Intestines; Knowledge; Link; Mediating; Microbe; Modeling; Molecular; Multi-Drug Resistance; Mus; Natural Immunity; Nematoda; Nervous system structure; Neurons; Neuropeptides; Neurosecretory Systems; Neurotransmitters; Organism; Pathway interactions; Pattern; Pharyngeal structure; Phenotype; Plants; Proliferating; Proteins; Publishing; RNA Interference; Rattus; Reporter; Research; Research Personnel; Role; Salmonella enterica; Sepsis; Signal Pathway; Signal Transduction; Source; System; Testing; Tissues; Work; arm; base; immunogenic; innate immune function; microbial; microorganism; mutant; neural circuit; neuromechanism; novel; pathogen; positional cloning; public health relevance; response; scavenger receptor

DESCRIPTION (provided by applicant): The innate immune system of animals and plants has evolved to maintain a healthy "load" of endemic microorganisms. "Beneficial" commensals proliferate in various compartments of multicellular organisms; this is tolerated by the innate immune system. On the other hand, the innate immune system actively attempts (and, mostly succeeds) to suppress growth of harmful pathogens. Multiple signals from both host and microbe are integrated to produce an appropriate level of immunogenic response. Large gaps in our knowledge of the molecular and cellular coordination of pathogen response remain. The nematode Caenorhabditis elegans is a simple, genetically-tractable model host for the study of innate immunity. Recent work has demonstrated that the C. elegans protein CED-1, a homologue of mammalian scavenger receptors, regulates activation of the non-canonical unfolded protein response (UPR) during the host innate immune response. Moreover, it has been demonstrated that the nervous system, via the G-protein coupled receptor (GPCR) OCTR-1, controls CED-1-mediated immune responses. For this proposal, there are three specific Aims: 1) determine the spatial requirement for CED-1 activity during an innate immune response, 2) analysis of neural circuits that regulate innate immunity, and 3) characterization of pathways that regulate CED-1-dependent abu gene expression. This study will identify innate immune pathways upstream and downstream of OCTR-1/CED-1. This work will help in characterizing molecular pathways, cell autonomous and non-cell autonomous, that contribute to immunity to human pathogens and tolerance of microbial gut communities.

描述(申请人提供)：动植物的先天免疫系统已经进化，以维持地方性微生物的健康“负荷”。“有益的”共生体在多细胞生物体的不同隔间中增殖；这是先天免疫系统所容忍的。另一方面，先天免疫系统积极地尝试(并大多成功)抑制有害病原体的生长。来自宿主和微生物的多种信号被整合在一起，以产生适当水平的免疫原性反应。在我们对病原体反应的分子和细胞协调方面的知识仍然存在很大差距。秀丽线虫是研究天然免疫的一种简单的、遗传上易驯化的模式宿主。最近的研究表明，线虫CED-1蛋白是哺乳动物清道夫受体的同源物，在宿主天然免疫反应中调节非规范未折叠蛋白反应(UPR)的激活。此外，已证实神经系统通过G蛋白偶联受体OCTR-1控制CED-1介导的免疫反应。对于这一建议，有三个具体的目标：1)确定先天性免疫反应中CED-1活性的空间需求，2)分析调节先天性免疫的神经回路，以及3)表征调控CED-1依赖的ABU基因表达的途径。本研究将确定OCTR-1/CED-1上游和下游的天然免疫途径。这项工作将有助于表征分子途径，细胞自主和非细胞自主，有助于对人类病原体的免疫和微生物肠道群落的耐受性。