Mechanisms of the gut-brain axis that regulate innate immunity

调节先天免疫的肠脑轴机制

• 批准号: 10623925
• 负责人: Javier Elbio Irazoqui
• 金额: $ 42.7万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623925
• 关键词: Acceleration; Acetylcholine; Address; Afferent Neurons; Anatomy; Animals; Back; Behavior; Biological Models; Brain; Caenorhabditis elegans; Chemicals; Communicable Diseases; Communication; Complex; Development; Diagnostic; Disease; Environment; Event; Future; Gene Expression; Genes; Goals; Host Defense; Human; Immune; Infection; Inflammation; Inflammatory; Innovative Therapy; Intestines; Knowledge; Malignant Neoplasms; Mammals; Mediating; Metabolic syndrome; Microbe; Mission; Molecular; Natural Immunity; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurons; Organ; Organism; Physiology; Public Health; Regulation; Research; Resolution; Role; Signal Transduction; Therapeutic; Translating; United States National Institutes of Health; Vision; Work; defense response; detection platform; gut-brain axis; host-microbe interactions; human disease; human model; in vivo; in vivo Model; insight; interest; intestinal epithelium; microbial; microbiota; mouse model; pathobiont; pathogen; pathogenic bacteria; programs; success; targeted treatment; transcription factor; Acceleration; Acetylcholine; Address; Afferent Neurons; Anatomy; Animals; Back; Behavior; Biological Models; Brain; Caenorhabditis elegans; Chemicals; Communicable Diseases; Communication; Complex; Development; Diagnostic; Disease; Environment; Event; Future; Gene Expression; Genes; Goals; Host Defense; Human; Immune; Infection; Inflammation; Inflammatory; Innovative Therapy; Intestines; Knowledge; Malignant Neoplasms; Mammals; Mediating; Metabolic syndrome; Microbe; Mission; Molecular; Natural Immunity; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurons; Organ; Organism; Physiology; Public Health; Regulation; Research; Resolution; Role; Signal Transduction; Therapeutic; Translating; United States National Institutes of Health; Vision; Work; defense response; detection platform; gut-brain axis; host-microbe interactions; human disease; human model; in vivo; in vivo Model; insight; interest; intestinal epithelium; microbial; microbiota; mouse model; pathobiont; pathogen; pathogenic bacteria; programs; success; targeted treatment; transcription factor

This project addresses the mechanisms of the gut-brain axis by which animals interact with bacterial pathogens and their microbiota. The focus is on mechanisms by which the nervous system detects the presence of distinct microbes, and communicates with the intestinal epithelium to elicit host defense responses. Also of interest is how the intestinal epithelium communicates back with the nervous system to modulate host physiology and behavior. Over the past ten years, our research program has used C. elegans as a whole-animal, in vivo model. The advantages of C. elegans include its relative anatomical simplicity and conserved signaling mechanisms, which enable sophisticated in vivo approaches to dissect inter-organ communication during infection. In this period, we have made fundamental discoveries including the outsized roles of TFEB-related transcription factors, acetylcholine-WNT brain-gut signaling, and pathogen-induced neurodegeneration (PaIN), all of which are conserved in mammals. Thus, our prior research has contributed to the fundamental understanding of host-microbe interactions and opened new avenues of research. The present project builds on our prior success and on our new insights into the involvement of sensory neurons and neurodegeneration in the host-microbe interaction. The goals for the next five years are to elucidate the neuronal mechanisms of microbial sensing in complex environments, understand the mechanisms of PaIN, and elucidate the mechanisms of regulation of intestinal host defense genes via TFEB-related transcription factors by the nervous system, in vivo. Longer term, the overall vision is to produce a comprehensive understanding of organismal, cellular, and molecular events that take place during initiation and resolution of infection by pathogens and pathobionts in C. elegans, and to capitalize on the present and future success of this project by continuing to translate our fundamental findings to murine and human model systems of infection and inflammation. Because of its focus on the gut-brain axis and the evolutionary conservation of the mechanisms that we have uncovered, the project is relevant to a broad range of human diseases and conditions, including infections, immune-mediated diseases, neurodegenerative diseases, metabolic syndrome, and cancer. We anticipate that the knowledge gained from the proposed work will advance the field and be generally applicable to higher organisms, and thus inform the search for better therapeutics and diagnostics for human infections and inflammation.

该项目解决了动物与细菌相互作用的肠道轴的机制 病原体及其菌群。重点是神经系统检测到的机制 存在不同的微生物，并与肠上皮进行通信以引起宿主防御 回答。有趣的是，肠上皮如何与神经系统进行回信 调节宿主生理和行为。在过去的十年中，我们的研究计划使用了秀丽隐杆线虫 作为整个动物，体内模型。秀丽隐杆线虫的优势包括其相对的解剖学简单性和 保守的信号传导机制，可以使体内复杂的方法进行剖析 感染期间的交流。在此期间，我们做出了基本发现 与TFEB相关的转录因子的作用，乙酰胆碱-Wnt脑浓度信号和病原体诱导的作用 神经变性（疼痛），所有这些都在哺乳动物中保守。因此，我们先前的研究做出了贡献 对宿主 - 微生物相互作用的基本了解，并开辟了新的研究途径。这 目前的项目基于我们先前的成功以及我们对感官神经元参与的新见解 和宿主微叶片相互作用中的神经变性。接下来五年的目标是阐明 在复杂环境中微生物感测的神经元机制，了解疼痛的机制， 并通过TFEB相关转录阐明肠道宿主防御基因调节的机制 神经系统的因素，体内。从长远来看，总体愿景是产生全面的 理解在开始和解决过程中发生的生物，细胞和分子事件 秀丽隐杆线虫中的病原体和病原体感染，并利用目前和未来的成功 该项目通过继续将我们的基本发现转化为鼠和人类模型系统 感染和炎症。因为它的重点是肠脑轴和对肠道的进化保护 我们发现的机制，该项目与广泛的人类疾病有关 病情，包括感染，免疫介导的疾病，神经退行性疾病，代谢 综合征和癌症。我们预计从拟议的工作中获得的知识将推动 野外并通常适用于更高的生物，从而告知寻找更好的治疗剂和 人类感染和炎症的诊断。