Functional mapping of enteric-associated neurons

肠相关神经元的功能图谱

• 批准号: 9765299
• 负责人: Daniel S Mucida
• 金额: $ 41.36万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765299
• 关键词: Architecture; Behavior; Brain; Cell Separation; Cells; Chronic; Classification; Code; Complex; Coupled; Diet; Diffuse; Dimensions; Disease; Distant; Enteral; Enteric Nervous System; Environmental Monitoring; Functional disorder; Gastrointestinal tract structure; Gene Expression Profiling; Genetic; Genetic Transcription; Glucose; Heterogeneity; Human; Image; Imagery; Immune; Immune response; Impairment; Inflammation; Inflammatory; Interneurons; Intestinal Content; Intestines; Irritable Bowel Syndrome; Large Intestine; Lead; Length; Light; Maintenance; Maps; Microbe; Monitor; Motor; Mucous Membrane; Multiple Sclerosis; Mus; Myography; Neuraxis; Neuronal Dysfunction; Neurons; Norepinephrine; Pathology; Pathway interactions; Peripheral Nervous System; Physiology; Play; Population; Process; Property; Reporter; Role; Salmonella infections; Sampling; Seminal; Sensory; Series; Side; Signal Transduction; Small Intestines; Stimulus; Structure; Surface; Techniques; Temperature; Time; Tissues; Translating; Translations; Viral; Work; arm; beta-2 Adrenergic Receptors; density; experience; experimental study; innovation; insight; macrophage; memory encoding; microbial; nerve supply; neurochemistry; novel; novel strategies; novel therapeutics; response; ribosome profiling; spatiotemporal; tool; transcriptomics; treatment strategy

The enteric nervous system comprises a complex and widespread network within the gastrointestinal tract and is characterized by both intrinsic and extrinsic arms containing neuron bodies within and outside of the intestine, respectively. Consistent with their role in gut physiology, impaired EAN function can lead to pathologies associated with defective secretory and motor function and chronic inflammatory conditions. EANs cohabitate the intestinal tissue with large populations of immune cells and both, immune and neuronal cells are equipped with sensing mechanisms that monitor perturbations at the luminal surface. Bidirectional interactions between immune and neuronal cells have been documented at steady state and dysfunction in these interactions have been proposed to be part of several disease processes, both local (e.g. irritable bowel syndrome) and systemic (e.g. multiple sclerosis). Despite its relevance for human physiology, the role played by EANs in tissue maintenance and pathology or how EANs communicate luminal insults to the local or distant tissues remains unclear. Novel approaches to gain genetic access to neuronal populations within the CNS have highlighted the transformative potential of these techniques. Surprisingly, little of the progress made in the study of the CNS has been translated into a significant understanding of the peripheral nervous system including EANs. By combining novel imaging and transcriptomic tools, our lab has developed extensive experience in understanding mucosal and intestinal immune responses, and our recent work has highlighted the role that EANs play in orchestrating immune responses. For instance, we uncovered an unexpected role for EANs in modulating a structurally coupled macrophage population via extrinsic sympathetic neuron-derived norepinephrine signaling through adrenergic receptor beta 2 (β2AR) on gut macrophages. To overcome obstacles in the study of EANs mentioned above, this proposal incorporates recent advances in cell-specific actively translating ribosome profiling, tissue clearing, opto- and chemo-genetic modulation of neuronal function as well as viral tracing in order to generate the first functional mapping of EANs, defining microbial sensing circuits in the intestine. Experiments proposed here will not only map this sensing circuit, but also establish tools to manipulate EAN activity to build a functional map of EANs in response to luminal challenges. Since we also propose to employ these novel techniques using human intestinal samples, the three- dimensional comparisons between mouse and human samples will yield insights not only into evolutionarily conserved mechanisms and pathways relevant to EAN architecture and behavior, but also add a strong translational component for understanding human intestinal physiology and pathology. The proposed project will thereby provide a much-needed platform to understand and explore novel therapeutic strategies for the treatment of disorders associated with inflammation-induced neuronal dysfunction.

肠神经系统由胃肠道内复杂且广泛的网络组成 其特征是内在臂和外在臂均包含神经元体内部和外部 肠，分别。与其在肠道生理学中的作用一致，EAN 功能受损可导致 与分泌和运动功能缺陷以及慢性炎症相关的病理。 EAN 肠道组织与大量免疫细胞共存，免疫细胞和神经细胞都 配备了监测管腔表面扰动的传感机制。双向互动 免疫细胞和神经元细胞之间的稳定状态和功能障碍已被记录在案 相互作用已被认为是多种疾病过程的一部分，无论是局部疾病（例如肠易激 综合征）和系统性（例如多发性硬化症）。尽管它与人类生理学相关，但它所发挥的作用 EAN 在组织维护和病理学中的作用，或者 EAN 如何将管腔损伤传达给本地或远端 组织仍不清楚。获得中枢神经系统内神经元群遗传途径的新方法 强调了这些技术的变革潜力。令人惊讶的是，进展甚微 对中枢神经系统的研究已转化为对周围神经系统的重要了解 包括 EAN。通过结合新颖的成像和转录组工具，我们的实验室开发了广泛的 在了解粘膜和肠道免疫反应方面的经验，我们最近的工作强调了 EAN 在协调免疫反应中发挥的作用。例如，我们发现了一个意想不到的角色 EAN 通过外源交感神经元调节结构耦合的巨噬细胞群 去甲肾上腺素通过肠道巨噬细胞上的肾上腺素受体 β2 (β2AR) 发出信号。克服 为了克服上述 EAN 研究中的障碍，该提案结合了细胞特异性的最新进展 积极翻译核糖体分析、组织清除、神经元的光和化学遗传调节 功能以及病毒追踪，以生成 EAN 的第一个功能图谱，定义微生物 肠道内的传感电路。这里提出的实验不仅会绘制该传感电路，而且还会绘制 建立工具来操纵 EAN 活动，以构建 EAN 功能图，以应对管腔挑战。 由于我们还建议使用人类肠道样本来采用这些新技术，因此这三项 小鼠和人类样本之间的尺寸比较不仅会产生进化方面的见解 与 EAN 架构和行为相关的保守机制和路径，而且还添加了强大的 用于理解人类肠道生理学和病理学的翻译组件。拟议项目 因此，将为理解和探索新的治疗策略提供一个急需的平台 治疗与炎症引起的神经元功能障碍相关的疾病。