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.

肠道神经系统包括胃肠道内的复杂而宽度的网络， 以内在和外在的臂的特征 肠道分别。与它们在肠道生理学中的作用一致，EAN功能受损可能导致 与缺陷的秘密和运动功能以及慢性炎症条件相关的病理。 Eans 与大量的免疫细胞以及免疫细胞和神经元细胞共同植入肠道组织 配备了敏感性机制，可以监测腔表面的扰动。双向相互作用 在稳态和神经元细胞之间已记录在稳态和功能障碍之间 已经提出相互作用是局部几个疾病过程的一部分（例如肠易激 综合征）和全身性（例如多发性硬化症）。尽管它与人类生理学相关，但角色扮演 通过组织维护和病理学中的EAN或EAN如何将管腔侮辱传达给局部或挑剔 组织仍然不清楚。新颖的方法以获得CNS内神经元种群的遗传获取 强调了这些技术的变革潜力。令人惊讶的是，几乎没有取得的进步 中枢神经系统的研究已转化为对周围神经系统的重大理解 包括Eans。通过结合新型成像和转录组工具，我们的实验室已经开发了广泛的 了解粘膜和肠道免疫反应的经验，我们最近的工作强调了 EANS在策划免疫反应中所扮演的角色。例如，我们发现了一个意外的角色 用于通过外部交感神经来调节结构耦合的巨噬细胞种群的EAN 肠道巨噬细胞上通过肾上腺素受体β2（β2AR）的去甲肾上腺素信号传导。克服 在上述EAN的研究中，该提案纳入了细胞特异性的最新进展 积极地翻译核糖体分析，组织清除，选择性和化学遗传调节神经元 功能以及病毒跟踪，以生成EAN的第一个功能映射，定义微生物 在肠中感应电路。这里提出的实验不仅会映射此感应电路，还会绘制 建立操纵EAN活动的工具，以构建EAN的功能图，以应对管腔挑战。 由于我们还建议使用人类肠道样品采用这些新技术，因此 小鼠和人类样品之间的维度比较将不仅会在进化中产生洞察力 与EAN结构和行为相关的保守机制和途径，但也增加了强大的 理解人类肠道生理学和病理学的翻译成分。拟议的项目 因此，将提供一个急需的平台，以了解和探索新颖的治疗策略 与炎症引起的神经元功能障碍有关的疾病的治疗。