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

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.

这个项目解决了动物与细菌相互作用的肠道-脑轴的机制。 病原体及其微生物区系。重点是神经系统通过哪些机制检测到 存在不同的微生物，并与肠道上皮联系以引发宿主防御 回应。同样令人感兴趣的是肠上皮如何与神经系统联系，以 调节宿主的生理和行为。在过去的十年里，我们的研究项目使用了线虫 作为一个整体动物，活体模型。线虫的优势包括相对解剖简单和 保守的信号机制，使复杂的体内方法能够解剖器官间 在感染过程中的交流。在这段时间里，我们有了根本性的发现，包括超大的 TFEB相关转录因子、乙酰胆碱-WNT脑肠信号转导和病原体诱导的作用 神经变性(疼痛)，所有这些在哺乳动物中都是保守的。因此，我们之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。这个 目前的项目建立在我们之前的成功和我们对感觉神经元参与的新见解的基础上 以及宿主-微生物相互作用中的神经退化。未来五年的目标是阐明 复杂环境中微生物感知的神经元机制，了解疼痛的机制， 阐明了TFEB相关转录调控肠道宿主防御基因的机制 这些因素是由神经系统在体内产生的。从长远来看，我们的总体愿景是制定一个全面的 理解在发病和解决过程中发生的生物、细胞和分子事件 通过病原体和致病细菌在线虫中的感染，并利用目前和未来在 该项目通过继续将我们的基本发现转化为小鼠和人类模型系统 感染和炎症。因为它的重点是肠道-脑轴和进化保守的 我们已经发现的机制，该项目与广泛的人类疾病和 疾病，包括感染、免疫介导性疾病、神经退行性疾病、代谢 综合症和癌症。我们预计，从拟议工作中获得的知识将推动 该领域并普遍适用于高等生物，因此有助于寻找更好的治疗方法和 人类感染和炎症的诊断。