Genetic analysis of innate immunity using C. elegans

使用秀丽隐杆线虫进行先天免疫的遗传分析

• 批准号: 8462761
• 负责人: Alejandro Aballay
• 金额: $ 3.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462761
• 关键词: Abbreviations; Afferent Neurons; Animals; Boxing; C. elegans genome; Caenorhabditis elegans; Calcium; Cell Death; Cells; Characteristics; Collaborations; Colony-forming units; Communication; Cyclic GMP; Disease; Dissection; Endocrine; Exhibits; G-Protein-Coupled Receptors; Gated Ion Channel; Genes; Genetic; Genome; Green Fluorescent Proteins; Health; Host Defense; Human; Immune; Immune response; Immune system; Infection; Insulin; Invaded; Laboratories; Lead; Ligands; Light; Lipopolysaccharides; MAP Kinase Gene; MAPK14 gene; Mediator of activation protein; Microarray Analysis; Microbe; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monitor; Mutation; Natural Immunity; Nature; Nematoda; Nervous system structure; Neurons; Neuropeptide Y Receptor; Neuropeptides; Neurophysiology - biologic function; Neurosecretory Systems; Neurotransmitters; Organism; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Physiological Processes; Process; Public Health; RNA Interference; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Soluble Guanylate Cyclase; Stimulus; Surface; Synapses; System; Taxes; Technology; Tissues; Toll-like receptors; Work; base; design; genetic analysis; human MAPK14 protein; immune function; insight; loss of function; microbial; microbicide; microorganism; millisecond; mutant; neural circuit; neuromechanism; new therapeutic target; pathogen; pathogen exposure; prevent; promoter; receptor-mediated signaling; relating to nervous system; research study; response; sensor; transcription factor

Description (provided by applicant): This proposal describes experiments designed to elucidate the mechanism by which the nervous system regulates innate immunity in response to pathogen infection. Our work in Caenorhabditis elegans has led to the identification of mutants that exhibit aberrant responses when infected with different pathogens. Analysis of these C. elegans mutants deficient in immune responses is clarifying the roles of a variety of interacting and intersecting genetic pathways involved in immune responses highly conserved across species, including humans. The latest studies from our laboratory indicate that innate immunity in C. elegans is regulated by neurons expressing NPR-1, which is a G-protein-coupled receptor related to mammalian neuropeptide Y receptors. Our studies have demonstrated that a neural circuit involving NPR-1 functions to suppress innate immune responses. The immune inhibitory function requires a cyclic GMP-gated ion channel encoded by tax-2 and tax-4 as well as the soluble guanylate cyclase GCY-35. Furthermore, we showed that npr-1- and gcy-35-expressing sensory neurons actively suppress immune responses of non-neuronal tissues. A full-genome microarray analysis on animals with altered neural function due to mutation in npr-1 showed enrichment in genes that are markers of innate immune responses, including those regulated by a conserved PMK-1/p38 mitogen-activated protein kinase signaling pathway. This proposal will continue our studies utilizing a C. elegans model to clarify the role of the nervous system in the regulation of innate immunity against bacterial pathogens. We hypothesize that G-protein coupled receptors (GPCRs) may participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate innate immune responses. There are three specific aims: 1) Identification of neurons expressing GPCRs that regulate innate immunity. 2) Dissection of the neural circuit that regulates innate immunity. 3) Identification and characterization of signals involved in neural- immune communications. The proposed studies will serve as a roadmap to understand the mechanisms by which the nervous and immune systems communicate through bidirectional signals. Given the conserved nature of neural communications and innate immune responses, we expect our work will lead to a better understanding of the mechanisms by which the metazoan nervous and innate immune systems influence each other. PUBLIC HEALTH RELEVANCE: We plan to continue our studies to clarify the role of the nervous system in the regulation of innate immune responses against bacterial pathogens. A better understanding of the neural-immune communication could lead to new therapeutic targets for diseases involving a deficient innate immune system.

描述（由申请人提供）：该提案描述了旨在阐明神经系统调节对病原体感染的先天免疫的机制的实验。我们在秀丽隐杆线虫中的工作导致了突变体在感染不同病原体时表现出异常反应的突变体。对这些秀丽隐杆线虫突变体缺乏免疫反应的分析正在阐明各种相互作用和相交的遗传途径在包括人类在内的物种高度保守的免疫反应中所涉及的遗传途径。我们实验室的最新研究表明，秀丽隐杆线虫中的先天免疫受到表达NPR-1的神经元的调节，NPR-1是与哺乳动物神经肽Y受体有关的G蛋白偶联受体。我们的研究表明，涉及NPR-1功能抑制先天免疫反应的神经回路。免疫抑制功能需要循环GMP门控离子通道，该通道由TAX-2和TAX-4以及可溶性鸟烯基环化酶GCY-35进行编码。此外，我们表明表达NPR-1-和GCY-35的感觉神经元可积极抑制非神经组织的免疫反应。对NPR-1突变引起的神经功能改变的动物的全基因组微阵列分析显示，在基因中富集是先天免疫反应的标志物，包括由保守的PMK-1/p38促促促促促PMK-1/p38促促促促细裂蛋白激活蛋白激酶信号途径的富集。该提案将利用秀丽隐杆线虫模型继续我们的研究来阐明神经系统在调节先天免疫对细菌病原体中的作用。我们假设G蛋白偶联受体（GPCR）可能参与接收来自病原体或感染部位输入的神经回路，并整合它们以协调适当的先天免疫反应。有三个特定的目的：1）表达调节先天免疫力的GPCR神经元的鉴定。 2）调节先天免疫的神经回路。 3）识别和表征与神经免疫通信有关的信号。拟议的研究将作为了解神经和免疫系统通过双向信号进行通信的机制的路线图。鉴于神经通信和先天免疫反应的保守性质，我们希望我们的工作将更好地理解后生动物神经和先天免疫系统相互影响的机制。公共卫生相关性：我们计划继续我们的研究，以阐明神经系统在调节对细菌病原体的先天免疫反应中的作用。对神经免疫传播的更好理解可能会导致涉及不良先天免疫系统的疾病的新治疗靶点。