Nitrergic Neuro-smooth Muscle Transmission in the Gut

肠道中的氮能神经平滑肌传递

• 批准号: 8067143
• 负责人: Raj K Goyal
• 金额: $ 26.44万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067143
• 关键词: Animal Model; Antibodies; Biliary; Binding; CaMKII phosphatase; Calcineurin; Complex; Constipation; Deglutition; Diabetes Mellitus; Disease; Dislocations; Dyspepsia; Enteral; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Food; Functional disorder; Gases; Gastrointestinal Motility; Gastrointestinal tract structure; Gastroparesis; Generations; Genetic; Heartburn; Impairment; Inbred NOD Mice; Intestines; Investigation; Irritable Bowel Syndrome; MYO5A gene; Membrane; Motor; Mus; Muscle; Myosin ATPase; N-Type Calcium Channels; Nerve; Neurotransmitters; Nitric Oxide; Nitroxidergic Nerves; Pancreas; Peristalsis; Physiological; Play; Production; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Regulation; Relaxation; Reporting; Role; Site; Smooth Muscle; Spasm; Sphincter; Varicosity; calmodulin-dependent protein kinase II; chronic abdominal pain; diabetic gastroparesis; dimer; gastrointestinal; gastrointestinal function; inhibitor/antagonist; motility disorder; mouse model; neuroregulation; neurotransmission; protein complex; public health relevance; transmission process

DESCRIPTION (provided by applicant): Nitric oxide (NO) is an important inhibitory neurotransmitter for the gastrointestinal smooth muscles. As a neurotransmitter, NO plays a key role in peristalsis and physiological relaxation of the sphincters and thus facilitates transport of food through the gastrointestinal tract. Loss of NO-related neurotransmission has been shown to cause diseases causing difficulty in swallowing, gastric stasis, dyspepsia, intestinal stasis and constipation. Defective NO neurotransmission is also implicated in diabetic gastroparesis and functional disorders of the gut such as irritable bowel syndrome and spasm of biliary and pancreatic sphincters. Nitric oxide is uniquely different from other classical neurotransmitters. Unlike the classical neurotransmitters, NO is a highly diffusible gas that is produced de novo on demand from Ca-CaM dependent activation of nNOS. However, regulation of NO generation and nitrergic neurotransmission is not well understood. We have recently shown that isolated nitrergic varicosities from mice gut contain inactive and active pools of nNOS. Dynamic regulation of the catalytically active nNOS1 is responsible for regulation of nitrergic neurotransmission. Overall purpose of the proposed studies is to extend our studies of regulation of catalytically active nNOS in the nitrergic varicosities and determine how nNOS is transported to the membrane, attached there and regulated to produce NO. We will use this information to identify abnormities in the steps that may impair nitrergic neurotransmission. These studies will help define pathophysiology of impaired nitrergic neurotransmission that have no anatomical evidence of loss or damage to nitrergic nerves. There are four specific aims: 1) To examine the role of PIN/LC8 and myosin Va in targeting nNOS to varicosity membrane and to investigate nitrergic neurotransmission in mice lacking myosin Va. 2) To examine the role of PSD proteins in membrane association of nNOS1 dimer and to investigate nitrergic neurotransmission with depalmitoylation of PSD and in mice lacking PSD 95. 3) To investigate the clustering of nNOS-PSD complex with N-type calcium channels and the enzymes that dephosphorylate or phosphorylate nNOS and to investigate the effects of inhibitors of these enzymes on nitrergic neurotransmission. 4) To investigate the mechanism of reduced inhibitory neurotransmission in an animal model of diabetes mellitus (NOD mice). PUBLIC HEALTH RELEVANCE: Gastrointestinal motility disorders result in a variety of diseases that cause difficulty in swallowing, heartburn, dyspepsia, constipation and chronic abdominal pain. This proposal is to understand how these disorders are caused and how better treatments for these disorders can be developed.

描述（由申请人提供）：一氧化氮（NO）是胃肠道平滑肌肉的重要抑制性神经递质。作为神经递质，NO在蠕动和括约肌的生理放松中起关键作用，因此促进了食物通过胃肠道的运输。已证明无关神经传递的丧失会导致疾病导致吞咽困难，胃停滞，消化不良，肠停滞和便秘。有缺陷的无神经传递也与糖尿病性胃癌和肠道功能障碍有关，例如肠易激综合征以及胆道和胰腺括约肌的痉挛。一氧化氮与其他经典神经递质的独特不同。与经典的神经递质不同，NO是一种高度扩散的气体，它是由NNOS的CA-CAM依赖性激活从开始需求产生的。但是，对没有一代和硝化神经传递的调节尚不清楚。我们最近表明，来自小鼠肠道的分离氮素静脉曲张含有非活性和活性池的NNOS。催化活性NNOS1的动态调节负责硝化神经传递的调节。拟议的研究的总体目的是扩展我们对硝化静脉曲张中催化活性NNO的调节的研究，并确定如何将NNOS运输到膜上，并附着在那里并进行调节以生产NO。我们将使用此信息来确定可能损害硝化神经传递的步骤中的异常。这些研究将有助于定义硝化神经传递受损的病理生理学，这些神经传递没有解剖学证据表明损失或对硝化神经的损害。有四个具体的目的：1）检查针对NNO在靶向NNOS靶向Varicosity膜的作用，并研究缺乏肌球蛋白VA的小鼠中硝化神经递质。 PSD95。3）研究NNOS-PSD复合物与N型钙通道的聚类和脱磷酸化或磷酸化NNOS的酶，并研究这些酶对硝基抗神经传输的抑制剂的影响。 4）研究糖尿病（NOD小鼠）动物模型中抑制性神经传递降低的机制。 公共卫生相关性：胃肠道运动障碍会导致多种疾病导致吞咽困难，胃灼热，消化不良，便秘和慢性腹痛。该建议是了解这些疾病是如何引起的，以及如何为这些疾病提供更好的治疗方法。