Using Electrochemical Methods to Probe Neuronal Signaling in the GI Tract

使用电化学方法探测胃肠道中的神经元信号传导

基本信息

批准号：
7895874
负责人：
GREG M SWAIN
金额：
$ 18.48万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-22 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895874
关键词：
Adolescent Adult Affect Age Animal Model Animal Testing Autonomic nervous system Behavior Therapy Binding Birth Blood Vessels Brain Cavia Child Childhood Colon Detection Development Diamond Digestive System Disorders Disease Dopamine Duodenum Dyspepsia Elderly Enteral Enteric Nervous System Esthesia Exhibits Family Functional Gastrointestinal Disorders Functional disorder Ganglia Gastroesophageal reflux disease Gastrointestinal Motility Gastrointestinal tract structure Genus Cola Goals Health Human In Vitro Intestines Irritable Bowel Syndrome Knowledge Lead Learning Measurement Measures Mediating Metabolism Methods Microelectrodes Muscle Myenteric Plexus Myxoid cyst Nerve Fibers Nervous System Part Nervous System Physiology Nervous system structure Neuroglia Neurons Neuropharmacology Neurotransmitters Newborn Infant Nitric Oxide Nitric Oxide Signaling Pathway Norepinephrine Paracrine Communication Pathogenesis Patients Peripheral Nervous System Pharmaceutical Preparations Prevalence Rattus Reflex action Reproducibility Research Resolution Scanning Serotonin Signal Pathway Signal Transduction Signaling Molecule Site Small Intestines Spinal Cord Submucous Plexus Techniques Testing Time Tissues Translating United States United States National Institutes of Health Work absorption age related base cell motility computerized data processing controlled release gastrointestinal gastrointestinal function ileum improved innovation insight interest motility disorder nerve supply nervous system development neurochemistry neuron development neuroregulation neurotransmission neurotransmitter release new technology postnatal prenatal public health relevance relating to nervous system response tool

项目摘要

DESCRIPTION (provided by applicant): Electrochemical methods with diamond microelectrodes will be used to investigate neuronal signaling pathways in the gut wall. These methods provide a direct measure of local concentration changes of electroactive neurotransmitters near the sites of release and action with high temporal resolution. Enteric neurons contain and release many neurotransmitters and some of these can be detected by electrochemical methods, in particular, serotonin (5-HT) and nitric oxide (NO). The extension of these techniques to the study of the peripheral nervous system constitutes an interesting and significant development. Many functional GI disorders, such as disturbances in motility, absorption/secretion and sensation that do not have an identifiable pathophysiological basis, are thought to be related to dysfunction in neurogenic signaling mechanisms. The proposed research will improve our understanding of the normal motility and secretory activities of the GI tract during postnatal maturation of the intestine. These studies will lead to the discovery of age specific pathophysiologic changes in neuronal signaling responsible for functional gut disorders that lead to disease. To this end, we will apply electrochemical methods of analysis with a diamond microelectrode, to investigate two functional questions: (i) can the excitatory neurotransmitter serotonin (5-HT) and the inhibitory neurotransmitter nitric oxide (NO) be measured in the small intestine and colon of test animals and can the associated neuropharmacology controlling release and clearance be understood, and (ii) how do the 5-HT and NO signaling pathways change with postnatal maturation of the ENS? Our goal is to identify the mechanisms controlling release and clearance of 5-HT and NO in the gut wall. We will conduct these studies in vitro in the myenteric and submucosal plexuses of the small intestine (ileum and duodenum) and colon of guinea pigs and a new SERT-KO rat animal model. We also propose to expand the scope of the studies to include dopamine (DA) and norepinephrine (NE) released in the myenteric plexus. These studies, which have significant relevance for pediatric health, will be performed as a function of test animal (guinea pig) age in order to learn about the postnatal ENS development. A better understanding of neural signaling pathways in GI health and disease can be gained through measurements of local neurotransmitter concentrations in the gut wall with high spatial and temporal resolution. PUBLIC HEALTH RELEVANCE: The research will investigate the postnatal development of neuronal signaling in the gut wall that controls muscular function. This will be accomplished through in vitro electrochemical measurements of neurotransmitter concentration changes made near the sites of release and action. These studies will provide new insights into potential pathophysiological changes responsible for pediatric GI motility disturbances that would persist into adulthood and would be responsible for the prevalence of functional GI disorders in the United States.

描述（由申请人提供）：带有钻石微电极的电化学方法将用于研究肠壁中的神经元信号通路。这些方法提供了直接衡量局部浓度变化的局部浓度变化，并在释放部位附近具有高时间分辨率的作用。肠神经元包含并释放许多神经递质，其中一些可以通过电化学方法（尤其是5-羟色胺（5-HT）和一氧化氮（NO）检测到。将这些技术扩展到周围神经系统的研究构成了有趣而重要的发展。许多功能性GI疾病，例如运动性障碍，没有可识别的病理生理基础的吸收/分泌和感觉，被认为与神经源信号传导机制的功能障碍有关。拟议的研究将提高我们对肠结构期间胃肠道的正常运动和分泌活动的理解。这些研究将导致在导致导致疾病的功能性肠道疾病的神经元信号传导中发现年龄特异性的病理生理变化。为此，我们将使用钻石微电极采用电化学分析方法来研究两个功能性问题：（i）兴奋性神经递质5-ht（5-HT）和抑制性神经递质一氧化氮（NO）可以在小型的小intestine中测量和测试动物的结肠以及相关的神经药理控制控制和清除率，（ii）5-HT和没有信号通路随着ENS的产后成熟而变化？我们的目标是确定控制5-HT的释放和清除的机制，而在肠壁上则没有。我们将在小肠（肠和十二指肠）和豚鼠的结肠和新的Sert-ko大鼠动物模型的小肠（Ileum和Duodenum）和结肠上进行体外进行这些研究。我们还建议扩大研究范围，包括在肌植物丛中释放的多巴胺（DA）和去甲肾上腺素（NE）。这些研究与小儿健康具有重要意义，将作为测试动物（豚鼠）年龄的函数进行，以了解产后ENS发育。通过测量高空间和时间分辨率的肠壁中局部神经递质浓度，可以更好地了解胃肠道健康和疾病中神经信号通路。公共卫生相关性：研究将研究控制肌肉功能的肠壁上神经元信号传导的产后发展。这将通过在释放和作用部位附近进行的神经递质浓度变化的体外电化学测量来实现。这些研究将提供有关导致小儿胃肠道运动障碍的潜在病理生理变化的新见解，这些变化将持续到成年，并将导致美国功能性GI疾病的患病率。