The role of superoxide dismutase SOD-1 in microbe-gut-brain interaction

超氧化物歧化酶 SOD-1 在微生物-肠-脑相互作用中的作用

• 批准号: 9980948
• 负责人: Howard C Chang
• 金额: $ 33.81万
• 依托单位: ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980948
• 关键词: Adult; Affect; Aging; Animal Model; Area; Bacteria; Behavior; Brain; Caenorhabditis elegans; Calcium; Cataloging; Catalogs; Communication; Data; Disease; Elderly; Enzymes; Equilibrium; Genetic Models; Glutamate Receptor; Glutamates; Goals; Habitats; Ingestion; Intestines; Invertebrates; Knowledge; Lead; Mediating; Memory; Metabolism; Microbe; Modeling; Molecular; Nematoda; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurons; Neuropeptides; Neurosecretory Systems; Oxidative Stress; Pathologic; Patients; Peroxides; Physiology; Play; Production; Pseudomonas aeruginosa; Pyocyanine; Reactive Oxygen Species; Regulatory Pathway; Research; Role; Scaffolding Protein; Signal Transduction; Signaling Molecule; Site; Superoxide Dismutase; Superoxides; Surveys; Symptoms; Synapses; Virulence Factors; Work; aging population; avoidance behavior; behavioral response; dysbiosis; experimental study; genetic approach; glutamatergic signaling; gut microbes; gut microbiota; gut-brain axis; host-microbe interactions; microbial; neuropathology; neurophysiology; neurotransmission; new therapeutic target; novel; pathogen; pathogenic bacteria; reduce symptoms; relating to nervous system; response; sensor; superoxide dismutase 1; therapeutic target; trafficking; ubiquitin-protein ligase

Gut microbes play an important role in regulating host physiology and metabolism. Recent studies indicate that gut microbes affect memory formation and neurodegenerative disease manifestation. However, it is not fully understood how gut microbes influence gut–brain communication. The nematode C. elegans has a relatively simple nervous system and will readily ingest microbes from a petri dish. Therefore, C. elegans is a well-established model organism for studying the neural basis of behaviors and host–microbe interactions. By combining the two areas of research, we recently discovered that superoxide dismutase-1 (SOD-1), an enzyme that converts superoxide to less harmful peroxide, acts as a reactive sensor of reactive oxygen species in the nervous system and regulates the behavioral response to microbes. Our data indicate a previously unknown function of SOD-1 and suggest a potential role for SOD-1 in regulating microbe-induced gut–brain communication. In aim 1, we will determine how bacteria activate SOD-1. In aim 2, we will determine whether a neuropeptide functions as a signaling molecule between the gut and the nervous system to modulate the SOD-1 dependent response. In aim 3, we will define how SOD-1 and glutamatergic signaling regulate behavioral response to microbes. The proposed work will advance our knowledge in several ways. Our genetic model will open up a new research area for understanding the microbe-induced communication at the gut–brain axis. In addition, the proposed experiments will unveil new regulatory pathways of SOD-1. Our results may help to elucidate the underlying mechanisms of gut dysbiosis among elderly adults and patients with neurodegenerative diseases and may lead to the identification of potential therapeutic target.

肠道微生物在调节宿主的生理和代谢方面起着重要作用。最近 研究表明肠道微生物影响记忆形成和神经退行性疾病 表现。 然而，肠道微生物如何影响肠-脑还不完全清楚。 通信线虫C.线虫的神经系统相对简单， 很容易从培养皿中摄取微生物。因此，C. elegans是一个很好的模型 研究行为和宿主-微生物相互作用的神经基础。通过 结合这两个领域的研究，我们最近发现超氧化物歧化酶-1 超氧化物歧化酶（SOD-1），一种将超氧化物转化为危害较小的过氧化物的酶， 神经系统中的活性氧传感器，并调节行为反应 到微生物。我们的数据表明SOD-1的一个以前未知的功能，并提出了一个潜在的 SOD-1在调节微生物诱导的肠-脑通讯中的作用。 在目标1中，我们将确定细菌如何激活SOD-1。在目标2中，我们将确定一种神经肽 作为肠道和神经系统之间的信号分子， SOD-1依赖性反应。在目标3中，我们将定义SOD-1和谷氨酸能信号传导 调节对微生物的行为反应。拟议的工作将推进我们的知识， 几种方式。我们的遗传模型将为理解基因组学开辟一个新的研究领域。 微生物引起的肠-脑轴交流。此外，建议的实验 将揭示SOD-1新的调控途径。我们的研究结果可能有助于阐明潜在的 老年人和神经退行性疾病患者肠道生态失调的机制 疾病，并可能导致识别潜在的治疗靶点。