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: 10590711
• 负责人: Dennis H Kim
• 金额: $ 44.25万
• 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/10590711
• 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; Neurons; Neurosecretory Systems; Organism; Pathogenesis; Pathway interactions; Physiology; Pseudomonas aeruginosa; Regulation; Research; Sensory; Signal Transduction; Stress; 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; secondary metabolite

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.

项目摘要 自2007年以来，NIGMS支持的我们的研究计划的长期目标一直是 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， 随着人们对简单动物宿主的研究的期待，将提供有关互动的见解 微生物和更复杂的动物宿主。我们带来了广泛的跨学科观点 实验方法基于秀丽隐杆线虫的分子遗传学，对已经跨越的研究 先天免疫的进化保守途径，与感染和连接的综合生理学 对压力的细胞和生物反应的免疫力，以及与微生物的相互作用如何影响 秀丽隐杆线虫的神经元信号传导和行为。我们最近的重点以及该项目的主要目标 接下来的五年是了解细菌如何影响神经系统的信号和行为。 秀丽隐杆线。我们已经描述了如何由特定的毒力相关的二级代谢产生的 致病细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 对于微生物代谢物可以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提示如何融合神经内分泌的调节 基因表达，揭示了控制决策的投入的层次调节 秀丽隐杆线虫的行为。定义了分子途径，涉及对P的先天识别。 感觉神经系统的铜绿选择，我们将继续采用系统的遗传方法来转动我们的 注意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 确定其他遗传和神经元途径，这些途径不仅是由宿主相互作用调节的 致病细菌，例如铜绿假单胞菌，也可以在近距离鉴定出的细菌种类 与秀丽隐杆线虫在其自然环境中的关联。我们期望遗传和整体实验 简单的秀丽隐杆线虫主持人的障碍性将使我们能够对如何进行全面分析 微生物代谢物在神经系统上起作用，以调节神经内分泌生理和行为。这 微生物群及其代谢产物越来越涉及体内平衡的各个方面 宿主动物疾病的发病机理。我们预计我们对秀丽隐杆线虫的研究将对 理解其他宿主生物体中宿主 - 微生物相互作用。