Comprehensive Structural and Functional Mapping of Mammalian Colonic Nervous System

哺乳动物结肠神经系统的全面结构和功能图谱

• 批准号: 9776992
• 负责人: YVETTE FRANCE TACHE
• 金额: $ 247.51万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-16 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9776992
• 关键词: 3-Dimensional; Affect; Afferent Neurons; American; Anatomy; Animal Model; Animals; Anus; Blood; Cell Communication; Cell physiology; Cells; Chemicals; Chronic; Clostridium difficile; Colitis; Colon; Colonic Diseases; Confocal Microscopy; Constipation; Data; Development; Diarrhea; Disease; Diverticulitis; Efferent Neurons; Electric Stimulation; Electrophysiology (science); Endocrine; Endocrine system; Enteral; Enteric Nervous System; Epithelium; Esthesia; Exons; Expression Profiling; Family suidae; Fiber Optics; Foundations; Functional disorder; Genes; High Prevalence; Homeostasis; Human; Image; Immune; Immunohistochemistry; Inflammation; Inflammatory Bowel Diseases; International; Interstitial Cell of Cajal; Intervention; Irritable Bowel Syndrome; Knowledge; Lasers; Light; Malignant Neoplasms; Manometry; Maps; Measurement; Methodology; Methods; Microdissection; Microelectrodes; Microscopy; Modality; Molecular; Morbidity - disease rate; Motor; Mucous Membrane; Mus; Muscle; Muscle Cells; Nerve; Nerve Fibers; Nervous system structure; Neuraxis; Neuroanatomy; Neuroglia; Neurons; Operative Surgical Procedures; Oral; Organ; Parkinson Disease; Pathway interactions; Patients; Pattern; Pelvis; Physiological; Play; Population; Potentiometry; Property; Public Health; Quality of life; Rattus; Receptor Signaling; Research Personnel; Resolution; Role; Sensory; Signal Transduction; Site; Spinal; Spinal Ganglia; Spinal cord injury; System; Systems Integration; Techniques; Technology; Three-Dimensional Image; Three-Dimensional Imaging; Tissues; Transgenic Organisms; Trauma; Viral; Visceral; Visceral pain; age related; animal tissue; base; cell motility; cost; design; effective therapy; electric impedance; human tissue; immune function; in vivo; innovation; interdisciplinary approach; laser capture microdissection; molecular phenotype; mortality; motility disorder; multidisciplinary; nerve supply; neural circuit; neurochemistry; neuroimaging; neuromuscular transmission; neuronal circuitry; neuroregulation; novel strategies; novel therapeutic intervention; optogenetics; pain sensation; receptive field; receptor; relating to nervous system; response; sensory system; targeted treatment; therapeutic target; tool; transcriptome sequencing; transmission process; voltage sensitive dye

ABSTRACT The colon is the site of a multitude of disorders which are leading causes of morbidity and mortality and of significant financial burden. The colonic intrinsic (enteric) and extrinsic innervation play crucial role in regulating the secreto-motor, endocrine, immune functions and pain sensation. There has been increasing understanding of the neurochemical and electrophysiological properties, cell physiology, and functional roles of colonic enteric neurons and their interaction with the parasympathetic, sympathetic and sensory systems during the past decades. However, these data are derived largely from small animal studies and relevant knowledge in large animals and humans is lagging, which has hampered the development of effective therapies. Recent advances in cutting edge approaches including 3-D mapping, innovative viral tracing tools, and neuroimaging provide a means to obtain detailed information on neural circuits and related functions in large animals and human tissues, which has never been achieved before. The overall objective of the proposal is to provide a comprehensive and detailed structural and functional mapping of the intrinsic and extrinsic innervation of various regions of the colon in humans and the pig, as a relevant large animal model based on its structural and physiological similarities to humans. Mice will be utilized for studies involving transgenic, optogenetics and viral tracing approaches. This objective will be achieved by a concerted effort of world expert investigators who developed state-of-the art neuroanatomical, molecular, electrophysiological and functional approaches. Preliminary data obtained by the consortium team showed the feasibility to use CLARITY, high resolution confocal microscopy, viral tracing and optogenetics to provide detailed mapping of extrinsic nerve fibers, enteric circuitries and the expertise to probe human colonic enteric neurons electrophysiologically by fast and high resolution neuroimaging. In addition, the design of new microelectrode array and fiber optic technology has allowed quantifying motor patterns in response to nerve stimulation at a resolution level not attained before. The combined effort and multidisciplinary approaches will fill the gaps in current knowledge on colonic intrinsic and extrinsic neuronal circuits and cell-cell communication, especially in human tissues and pig, a large animal model ideally suited for translational applicability to patients. These findings will set the foundation for understanding neurocircuitry in this organ and will be critical for potential electroceutical interventions to treat colonic disorders.

抽象的 结肠是多种疾病发生的场所，这些疾病是发病率和死亡率的主要原因。 重大的经济负担。结肠内在（肠）和外在神经支配在调节中起着至关重要的作用 分泌运动、内分泌、免疫功能和痛觉。人们的理解不断加深 结肠肠的神经化学和电生理学特性、细胞生理学和功能作用 过去神经元及其与副交感神经、交感神经和感觉系统的相互作用 几十年。然而，这些数据主要来自小动物研究和大样本的相关知识。 动物和人类的研究进展滞后，这阻碍了有效疗法的开发。最新进展 包括 3D 绘图、创新病毒追踪工具和神经影像学在内的尖端方法提供了 指获得大型动物和人体组织中神经回路和相关功能的详细信息， 这是以前从未实现过的。该提案的总体目标是提供全面且 结肠各个区域的内在和外在神经支配的详细结构和功能图 在人类和猪中，由于其结构和生理相似性，作为相关的大型动物模型 人类。小鼠将用于涉及转基因、光遗传学和病毒追踪方法的研究。这 目标将通过开发最先进技术的世界专家调查人员的共同努力来实现 神经解剖学、分子、电生理学和功能方法。初步数据由 联盟团队展示了使用 CLARITY、高分辨率共聚焦显微镜、病毒追踪和 光遗传学提供外在神经纤维、肠道回路的详细图谱和探测专业知识 通过快速、高分辨率神经成像对人结肠肠神经元进行电生理学分析。此外， 新的微电极阵列和光纤技术的设计允许量化响应的运动模式 以前所未有的分辨率水平进行神经刺激。共同努力和多学科 方法将填补当前关于结肠内在和外在神经元回路以及细胞间知识的空白 交流，特别是在人体组织和猪（一种非常适合转化的大型动物模型）中 对患者的适用性。这些发现将为理解该器官的神经回路奠定基础 对于治疗结肠疾病的潜在电疗法至关重要。