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

基本信息

批准号：
10008153
负责人：
YVETTE FRANCE TACHE
金额：
$ 262.71万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
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/10008153
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 Financial Hardship 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 Structure 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

项目摘要

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的所在地，这些疾病是发病率和死亡率的主要原因巨大的财务负担。结肠内在（肠）和外部神经神经在调节中起着至关重要的作用秘密运动，内分泌，免疫功能和疼痛感。越来越多的理解神经化学和电生理特性，细胞生理学以及结肠肠的功能作用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。但是，这些数据主要来自小型动物研究和相关知识动物和人类正在落后，这阻碍了有效疗法的发展。最近的进步在尖端方法中，包括3-D映射，创新的病毒跟踪工具和神经影像学提供了获得有关大型动物和人体组织中神经回路和相关功能的详细信息的手段，这从未有过。该提案的总体目的是提供全面的和详细的结构和功能映射的结构和外在神经的固有和外在神经支配的各个区域在人类和猪中，作为基于其结构和生理相似性的相关大型动物模型人类。小鼠将用于涉及转基因，光遗传学和病毒追踪方法的研究。这世界专家调查员的共同努力将实现目标，他们开发了最先进神经解剖学，分子，电生理和功能方法。由财团团队表现出使用清晰度，高分辨率共聚焦显微镜，病毒追踪和的可行性光遗传学可提供外在神经纤维，肠电路和专业知识的详细映射以探测通过快速和高分辨率神经成像在电生理上进行人体结肠肠神经元。另外，新的微电极阵列和光纤技术的设计允许量化运动模式以响应在分辨率水平上无法达到的神经刺激。综合努力和多学科方法将填补有关结肠内在和外部神经元电路的当前知识和细胞细胞的空白交流，尤其是在人体组织和猪中，一种大型动物模型，非常适合翻译适用于患者。这些发现将为理解该器官中的神经记录奠定基础，并对于治疗结肠疾病的潜在电内干预措施至关重要。