Neural regulation of innate immunity to pathogen infection in C.elegans

线虫病原体感染先天免疫的神经调节

基本信息

批准号：
9279044
负责人：
Jingru Sun
金额：
$ 18.86万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279044
关键词：
Address Afferent Neurons Alzheimer&apos s Disease American Society of Hematology Animal Model Atherosclerosis Autoimmune Diseases Behavioral Binding Biogenic Amines Biological Neural Networks Caenorhabditis elegans Calcium Catecholamines Cells Cellular Stress Chemical Stimulation Chronic Communication Complement Complex Crohn&apos s disease Cues Development Diabetes Mellitus Disease Enzymes G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gap Junctions Gene Expression Genes Genetic Genomics Glean Health Human Image Immune Immune System Diseases Immune response Immune signaling Immune system Immunity In Vitro Individual Infection Inflammatory Innate Immune Response Insecta Interneurons Ligands Link Mediating Mediation Mixed Function Oxygenases Molecular Analysis Molecular Genetics Mus Natural Immunity Nematoda Nervous System control Nervous system structure Neuromodulator Neurons Neuropeptides Neurotransmitters Octopamine Pathologic Pathway interactions Physiological Play Process Production Rattus Regulation Regulatory Pathway Rheumatoid Arthritis Role Signal Pathway Synapses System Therapeutic Tyramine behavioral response effective therapy environmental change genetic approach immunoregulation improved killings microbial neural circuit neuromechanism neuroregulation neurotransmission pathogen receptor receptor function response

项目摘要

Project Summary/Abstract Upon pathogen infection, cellular stress pathways and microbial killing pathways are rapidly activated by the host immune system. These pathways must be tightly regulated as insufficient or excessive immune responses have deleterious consequences. Recent studies indicate that the nervous system plays a critical role in the regulation of immune responses. However, the precise mechanisms behind this regulation remain unclear. While many aspects of neural control of immunity are difficult to dissect in complex mammalian systems or in vitro, the nematode Caenorhabditis elegans has proven to be an excellent model organism for studying such control due to its simple, well-defined nervous system and accessibility to genetic, genomic, and molecular analyses. Our recent studies demonstrated that OCTR-1, a putative G protein-coupled receptor for catecholamines, functions in two sensory neurons ASH and ASI to suppress innate immunity by inhibiting immune signaling pathways. These findings highlight the importance of specific genes and neurons in the regulation of immunity. Two important questions, however, remain unanswered. First, what is the ligand that activates OCTR-1 in the sensory neurons? Second, which neurons form circuits with ASH and ASI to control the innate immune responses? In the current proposal, we seek to answer both questions. We will use a variety of molecular and genetic approaches to identify OCTR-1 ligand(s) and assess the roles of candidate neurons in the OCTR-1 neural circuit. The proposed studies will uncover molecules and cells involved in the activation and mediation of the OCTR-1-dependent neural signaling, which will give us a better understanding of how the nervous system controls innate immunity. Dysregulation of innate immunity to pathogens has been linked to a number of pathological states in human, such as chronic inflammatory diseases and autoimmune diseases. Information gleaned from the proposed studies will be useful to the development of more effective treatments for innate immune disorders.

项目摘要/摘要病原体感染后，细胞应激途径和微生物杀伤途径迅速由宿主免疫系统激活。这些途径必须严格调节为不足或过度免疫反应会带来有害后果。最近的研究表明神经系统在免疫反应调节中起关键作用。但是，该法规背后的精确机制尚不清楚。而神经的许多方面在复杂的哺乳动物系统或体外，很难控制免疫力线虫秀丽隐杆线虫已被证明是研究的出色模型生物这种控制由于其简单，定义明确的神经系统和遗传的可及性，基因组和分子分析。我们最近的研究表明，OCTR-1，一种推定的G 儿茶酚胺的蛋白质偶联受体，在两个感觉神经元中的功能和ASI 通过抑制免疫信号通路来抑制先天免疫。这些发现突出了特定基因和神经元在免疫调节中的重要性。两个很重要但是，问题仍未得到答复。首先，在激活OCTR-1的配体是什么感觉神经元？第二，神经元与灰分和ASI形成电路以控制先天免疫反应？在当前的建议中，我们试图回答这两个问题。我们将使用一个鉴定OCTR-1配体的各种分子和遗传学方法并评估角色 OCTR-1神经回路中的候选神经元。拟议的研究将发现参与OCTR-1依赖性神经的激活和介导的分子和细胞信号传导，这将使我们更好地了解神经系统如何控制先天免疫。对病原体的先天免疫失调已与许多人类的病理状态，例如慢性炎症性疾病和自身免疫性疾病。从拟议的研究中收集的信息将有助于发展对先天免疫疾病的更有效治疗方法。