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：
8726994
负责人：
Alejandro Aballay
金额：
$ 33.66万
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/8726994
关键词：
Ablation Accounting Adrenergic Agents American Society of Hematology Animals Bacterial Infections C. elegans genome Caenorhabditis elegans Calcium Cells Characteristics Collaborations Communication Disease Endocrine G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genes Genetic Genetic Techniques 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 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 adrenergic design genetic analysis immune activation immune function insight microbial microbicide microorganism millisecond mutant neural circuit neuromechanism new therapeutic target pathogen pathogen exposure prevent protein folding public health relevance 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）：识别病原体后先天免疫系统的激活导致对入侵微生物的快速且明确的杀菌反应，该反应经过微调以防止反应中有害的缺陷或过度。越来越多的证据表明，免疫反应是通过反射性运作的神经回路快速协调的。然而，考虑到哺乳动物神经和免疫系统的复杂性，这两个系统相互影响的精确机制仍未得到充分研究。该提案描述了旨在阐明神经系统调节先天免疫机制的实验。利用线虫秀丽隐杆线虫，我们最近证明先天免疫不仅在细胞自主水平上受到调节，而且还通过表达 G 蛋白偶联受体的神经元在细胞非自主水平上受到调节。更具体地说，我们发现 NPR-1（一种与哺乳动物神经肽 Y 受体相似的 GPCR）参与控制秀丽隐杆线虫 p38/PMK-1 MAPK 通路的神经回路。我们实验室的其他研究表明，OCTR-1 是神经系统中表达的章鱼胺的肾上腺素 GPCR，它控制 p38/PMK-1 通路和非神经元组织中表达的未折叠反应通路，这对于缓解免疫激活过程中对蛋白质折叠的需求增加。具体来说，在这个提案中，我们将使用各种分子和遗传技术来探索一般假设，即在整个动物水平上，神经系统在宿主对病原体感染的反应过程中调节免疫稳态。鉴于先天免疫反应和神经系统中 GPCR 介导的信号传导的保守性，拟议的研究应该有助于更好地理解后生动物神经和先天免疫系统相互影响的一些机制。