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.

摘要