Microbial Modulation of Physiology and Behavior of C. elegans

微生物对线虫生理和行为的调节

• 批准号: 10205915
• 负责人: Dennis H Kim
• 金额: $ 33.05万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10205915
• 关键词: Afferent Neurons; Animal Behavior; Animals; Attention; Bacteria; Behavior; Caenorhabditis elegans; Chemicals; Complex; Cues; Decision Making; Detection; Disease; Environment; Gene Expression; Genetic; Goals; Homeostasis; Immunity; Infection; Ligands; Microbe; Molecular; Molecular Genetics; National Institute of General Medical Sciences; Natural Immunity; Nervous system structure; Neurons; Neurosecretory Systems; Organism; Pathogenesis; Pathway interactions; Physiology; Pseudomonas aeruginosa; Regulation; Research; Sensory; Signal Transduction; Stress; Transforming Growth Factor alpha; Transforming Growth Factor beta; Virulence; Work; avoidance behavior; behavior influence; behavioral response; genetic analysis; genetic approach; host-microbe interactions; insight; microbial; microbiota; neurotransmission; pathogenic bacteria; programs; response

Project Summary The long-term goals of our research program, which has been supported by NIGMS since 2007, has been to understand how host-microbe interactions influence the physiology and behavior of Caenorhabditis elegans, with the anticipation that studies of the simple animal host will provide insights into interactions between microbes and more complex animal hosts. We have brought a broad interdisciplinary perspective, with an experimental approach grounded in the molecular genetics of C. elegans, to studies that have spanned evolutionarily conserved pathways of innate immunity, the integrative physiology that connects infection and immunity with cellular and organismal responses to stress, and how interactions with microbes influence neuronal signaling and behavior of C. elegans. Our most recent focus, and the principal goal of this project over the next five years, is to understand how bacteria influence nervous system signaling and behavior of C. elegans. We have described how specific virulence-associated secondary metabolites produced by the pathogenic bacteria Pseudomonas aeruginosa can modulate expression of a TGF-beta ligand in a pair of sensory neurons of C. elegans to promote avoidance behavior, defining a genetic, neuronal, and chemical basis for the molecular mechanisms by which microbial metabolites can modulate host organism behavior. We have further determined how environmental and endogenous cues converge on the regulation of neuroendocrine gene expression, revealing insight into the hierarchical regulation of inputs that control decision-making behavior of C. elegans. Having defined the molecular pathways involved the innate recognition of P. aeruginosa by the sensory nervous system, we will continue to take a systematic genetic approach to turn our attention to the question of how infection and changes in internal state can modify neuroendocrine gene expression and behavior. We also plan to expand the scope of our studies in a more exploratory manner, to identify additional genetic and neuronal pathways that are modulated by host interactions with not only pathogenic bacteria such as P. aeruginosa, but also bacterial species that have been identified in close association with C. elegans in its natural environment. We expect that the genetic and overall experimental tractability of the simple C. elegans host will enable us to work towards a comprehensive analysis of how microbial metabolites act on the nervous system to modulate neuroendocrine physiology and behavior. The microbiota and its metabolites have been increasingly implicated in diverse aspects of homeostasis and the pathogenesis of disease in host animals. We anticipate our studies of C. elegans will have implications for the understanding of host-microbe interactions in other hosts organisms.

项目概要 我们的研究计划自 2007 年以来一直得到 NIGMS 的支持，其长期目标是 了解宿主-微生物相互作用如何影响秀丽隐杆线虫的生理和行为， 预计对简单动物宿主的研究将为了解不同宿主之间的相互作用提供见解 微生物和更复杂的动物宿主。我们带来了广泛的跨学科视角 基于线虫分子遗传学的实验方法，涵盖了跨领域的研究 先天免疫的进化保守途径，连接感染和免疫的综合生理学 细胞和有机体对应激反应的免疫力，以及与微生物的相互作用如何影响 线虫的神经信号和行为。我们最近的重点以及该项目的主要目标 未来五年的目标是了解细菌如何影响线虫的神经系统信号和行为。 线虫。我们已经描述了特定毒力相关的次级代谢产物是如何产生的 致病菌铜绿假单胞菌可以调节一对 TGF-β 配体的表达 秀丽隐杆线虫的感觉神经元促进回避行为，定义遗传、神经元和化学基础 了解微生物代谢物调节宿主生物行为的分子机制。我们有 进一步确定环境和内源性线索如何聚合神经内分泌的调节 基因表达，揭示控制决策的输入的层次调节 线虫的行为。定义了涉及 P 的先天识别的分子途径。 铜绿假单胞菌通过感觉神经系统，我们将继续采取系统的遗传方法来改变我们的 关注感染和内部状态变化如何改变神经内分泌基因的问题 表达和行为。我们还计划以更具探索性的方式扩大我们的研究范围， 确定通过宿主相互作用调节的其他遗传和神经元通路，不仅 病原菌，如铜绿假单胞菌，以及已在近距离鉴定的细菌种类 与自然环境中的秀丽隐杆线虫的关联。我们期望遗传和整体实验 简单的秀丽隐杆线虫宿主的易处理性将使我们能够努力全面分析如何 微生物代谢产物作用于神经系统，调节神经内分泌生理和行为。这 微生物群及其代谢物越来越多地涉及体内平衡和环境的各个方面 宿主动物疾病的发病机制。我们预计我们对线虫的研究将对 了解其他宿主生物体中宿主与微生物的相互作用。