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

基本信息

批准号：
9176598
负责人：
Alejandro Aballay
金额：
$ 5.96万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176598
关键词：
Ablation Accounting Adrenergic Agents American Society of Hematology Animals Bacterial Infections C. elegans genome CCL4 gene Caenorhabditis elegans Calcium Cells Characteristics Collaborations Communication Disease Endocrine G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genes Genetic Techniques Health Homeostasis Host Defense Immune Immune response Immune system Infection Inflammation Invaded Investigation Laboratories Lead Ligands Link MAP Kinase Gene MAPK14 gene Mammals Mediator of activation protein Metabolic Molecular Genetics Monitor Natural Immunity Nature Nematoda Nervous System control Nervous system structure Neurons Neuropeptide Y Receptor Neuropeptides Neurosecretory Systems Neurotransmitters Octopamine Organism Pathway interactions Pharmaceutical Preparations Physiological Physiological Processes Predisposition Process Publishing Regulation Role Signal Transduction Signaling Molecule Stimulus Surface Synapses System Technology Tissues design genetic analysis genetic approach immune activation immune function insight microbial microbicide microorganism millisecond mutant neural circuit neuromechanism new therapeutic target pathogen pathogen exposure prevent protein folding receptor receptor-mediated signaling relating to nervous system research study response sensor

项目摘要

DESCRIPTION (provided by applicant): Activation of the innate immune system upon pathogen recognition results in a rapid and definitive microbicidal response to invading microorganisms that is fine-tuned to prevent deleterious deficiencies or excesses in the response. Increasing evidence indicates that immune responses are rapidly coordinated by neural circuits that operate reflexively. However, given the complexity of the nervous and immune systems of mammals, the precise mechanisms by which the two systems influence each other remain understudied. This proposal describes experiments designed to elucidate the mechanism by which the nervous system regulates innate immunity. Using the nematode Caenorhabditis elegans, we have recently demonstrated that innate immunity is not only regulated at the cell autonomous level, but also at the cell non-autonomous level through neurons expressing G-protein-coupled receptors. More specifically, we found that NPR-1, a GPCR similar to mammalian neuropeptide Y receptors, participates in a neural circuit that controls the p38/PMK-1 MAPK pathway in C. elegans. Additional studies from our laboratory indicate that OCTR-1, which is an adrenergic GPCR for octopamine expressed in the nervous system, controls the p38/PMK-1 pathway and unfolded response pathways that are expressed in non-neuronal tissues and that are necessary to alleviate the increased demand on protein folding during immune activation. In this proposal specifically, we will use a variety of molecular and genetic techniques to explore the general hypothesis that the nervous system regulates immune homeostasis during host response to pathogen infections at the whole animal level. Given the conserved nature of innate immune responses and of GPCR-mediated signaling in the nervous system, the proposed studies should lead to a better understanding of some of the mechanisms by which the metazoan nervous and innate immune systems influence each other.

描述（由申请人提供）：病原体识别时先天免疫系统的激活导致对入侵微生物的快速，确定的微生物反应，这些反应是对微生物进行微调的，以防止有害的缺陷或反应中的过量。越来越多的证据表明，免疫反应被反射性运行的神经回路迅速协调。但是，鉴于哺乳动物的神经和免疫系统的复杂性，两种系统彼此影响的确切机制仍在研究中。该建议描述了旨在阐明神经系统调节先天免疫的机制的实验。使用线虫秀丽隐杆线虫，我们最近证明，先天免疫不仅受到细胞自主水平的调节，而且通过表达G蛋白偶联受体的神经元在细胞自主水平上进行了调节。更具体地说，我们发现NPR-1是类似于哺乳动物神经肽Y受体的GPCR，它参与了控制秀丽隐杆线虫中p38/pmk-1 MAPK途径的神经回路。我们实验室的其他研究表明，OCTR-1是在神经系统中表达的章鱼胺的肾上腺素能GPCR，它控制着在非神经组织中表达的p38/pmk-1途径和未折叠的响应途径，并且是减轻了所必需的，这些途径是减轻的。免疫激活期间对蛋白质折叠的需求增加。在此提案中，我们将使用各种分子以及探索一般假设的遗传技术，即神经系统在宿主对整个动物水平的病原体感染反应期间调节免疫稳态。鉴于神经系统中先天免疫反应和GPCR介导的信号传导的保守性质，拟议的研究应更好地理解后代神经和先天免疫系统相互影响的某些机制。