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: 10676724
• 负责人: Alejandro Aballay
• 金额: $ 2.6万
• 依托单位: OREGON HEALTH & SCIENCE 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676724
• 关键词: Animals; Caenorhabditis elegans; Communication; Cues; Disease; Endocrine; Genes; Goals; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Infection; Inflammation; Innate Immune Response; Innate Immune System; Instruction; Intestines; Mammals; Metabolic; Natural Immunity; Nematoda; Nervous System; Neurons; Neurosecretory Systems; Neurotransmitters; Pathogenicity; Pathologic; Pathway interactions; Physiological; Physiology; Play; Regulation; Role; Signal Transduction; Site; Tissues; Travel; communication behavior; genetic analysis; genetic approach; gut colonization; immune activation; immunoregulation; microbiota; neural; neural circuit; new therapeutic target; next generation; pathogen; pathogen exposure; pathogenic bacteria; response; transmission process

Increasing evidence suggests that the intestine plays an important role in sensing not only the presence of pathogens but also changes in the microbiota, which ultimately result in changes in the regulation of immune pathways and behaviors by communicating with neurons. However, the complexity of the nervous and immune systems of mammals makes it difficult to dissect the mechanisms by which the neural-gut axis communicates using bidirectional signals to control intestinal immunity. Studies in the nematode Caenorhabditis elegans show that bacterial colonization of the intestine results in the activation of the expression of innate immune genes in the gut and the activation of a neuroendocrine signal that controls pathogen avoidance. The germline also plays a key role in the neural-gut axis not only by transmitting the immunological memory to the next generation but also by communicating pathogenic cues that travel from the gut to the nervous system to control innate immunity. The long-term goal of this proposal is to elucidate the mechanism by which the neural-germline-gut axis communicates to sense pathogens and/or infection-induced physiological changes to control innate immunity at the whole animal level. Thus, we will explore the general hypothesis that the neural-germline-gut axis plays a critical role in the organismal response against bacterial pathogens by helping the nervous system integrate signals from infected sites and different tissues to coordinate the immune response. Specific genes and neurons will be studied to dissect the neural circuits that regulate immune activation in response to pathogen exposure and pathogen-induced alterations of the animal’s physiology. A genetics approach will also be used to identify neurotransmitters and endocrine signals potentially involved in the neural-immune communication that takes place between neurons and different tissues and infected sites. RELEVANCE (See instructions): The systemic control of innate immunity is critical because inflammation accounts for the major physiological, metabolic, and pathological responses to infections. We plan to continue our studies to clarify the role of the nervous system in the regulation of intestinal 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.

越来越多的证据表明，肠道不仅在感知 病原体的变化，但也在微生物群的变化，这最终导致在调节的变化， 免疫途径和行为通过与神经元通信。然而， 哺乳动物的神经和免疫系统使得很难剖析其机制， 神经-肠轴使用双向信号进行通信以控制肠道免疫。的研究 线虫秀丽隐杆线虫表明，肠道的细菌定植导致 激活肠道中先天免疫基因的表达和激活神经内分泌 控制病原体回避的信号。生殖细胞在神经-肠轴中也起着关键作用， 不仅通过将免疫记忆传递给下一代， 从肠道传播到神经系统以控制先天免疫的致病线索。长期 这项计划的目的是阐明神经-生殖细胞-肠轴之间的通讯机制 以感测病原体和/或感染诱导的生理变化，从而控制先天免疫， 全动物水平。因此，我们将探讨神经-生殖细胞-肠轴在 通过帮助神经系统， 整合来自感染部位和不同组织的信号以协调免疫反应。具体 基因和神经元将被研究，以解剖调节免疫激活的神经回路， 对病原体暴露的反应和病原体诱导的动物生理学改变。一 遗传学方法也将用于识别神经递质和内分泌信号， 参与神经元和不同组织之间的神经免疫通讯 和受感染的网站。 相关性（参见说明）： 先天免疫的系统性控制是至关重要的，因为炎症占主要的 对感染的生理、代谢和病理反应。我们计划继续研究， 神经系统在调节肠道天然免疫应答中的作用 病原体更好地了解神经免疫通讯可能会导致新的治疗方法 涉及先天免疫系统缺陷的疾病的靶点。