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.

本项目旨在研究动物与细菌相互作用的肠-脑轴机制。 病原体及其微生物群。重点是神经系统检测神经元的机制。 存在不同的微生物，并与肠上皮细胞沟通，引发宿主防御 应答同样令人感兴趣的是肠上皮细胞如何与神经系统沟通， 调节宿主的生理和行为。在过去的十年里，我们的研究计划使用C。elegans 作为整体动物的体内模型。C.包括其相对简单的解剖结构， 保守的信号传导机制，这使得复杂的体内方法能够解剖器官间 感染期间的沟通。在这一时期，我们有了一些重大发现， TFEB相关转录因子、乙酰胆碱-WNT脑肠信号传导和病原体诱导的 神经变性（PaIN），所有这些在哺乳动物中是保守的。因此，我们先前的研究有助于 对宿主-微生物相互作用的基本理解，并开辟了新的研究途径。的 目前的项目建立在我们先前的成功和我们对感觉神经元参与的新见解的基础上 和神经变性的影响。未来五年的目标是阐明 复杂环境中微生物传感的神经元机制，了解PaIN的机制， 阐明TFEB相关转录调控肠道宿主防御基因的机制 在体内的神经系统的影响。从长远来看，总体愿景是制定一个全面的 了解在启动和解决过程中发生的有机体，细胞和分子事件， C.中病原体和致病菌的感染。优雅，并利用现在和未来的成功， 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。由于其重点是肠-脑轴和进化保守的 根据我们发现的机制，该项目与广泛的人类疾病有关， 病症，包括感染、免疫介导的疾病、神经退行性疾病、代谢性疾病、 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 领域，并普遍适用于高等生物，从而为寻找更好的治疗方法提供信息， 用于人类感染和炎症的诊断。