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）是胃肠平滑肌的重要抑制性神经递质。作为一种神经递质，NO在括约肌的扩张和生理松弛中起关键作用，从而促进食物通过胃肠道的运输。NO相关的神经传递的丧失已被证明会引起引起吞咽困难、胃停滞、消化不良、肠停滞和便秘的疾病。有缺陷的NO神经传递也与糖尿病性胃轻瘫和肠道功能障碍如肠易激综合征和胆胰括约肌痉挛有关。一氧化氮是独特的不同于其他经典的神经递质。与经典的神经递质不同，NO是一种高度可扩散的气体，其根据Ca-CaM依赖性激活nNOS的需要重新产生。然而，NO的产生和氮能神经传递的调节还不清楚。我们最近发现，从小鼠肠道分离的氮能静脉曲张含有非活性和活性池的nNOS。具有催化活性的nNOS 1的动态调节负责调节氮能神经传递。拟议的研究的总体目的是扩大我们的研究的催化活性nNOS在氮能静脉曲张的调节，并确定如何nNOS被运送到膜，附着在那里，并调节产生NO。我们将使用这些信息来确定异常的步骤，可能会损害氮能神经传递。这些研究将有助于确定氮能神经传递受损的病理生理学，没有氮能神经损失或损伤的解剖学证据。有四个具体目标：1）研究PIN/LC 8和肌球蛋白Va在将nNOS靶向静脉曲张膜中的作用，并研究缺乏肌球蛋白Va的小鼠的氮能神经传递。2)研究PSD蛋白在nNOS 1二聚体膜结合中的作用，并研究PSD去棕榈酰化和PSD 95缺失小鼠的氮能神经传递。3)研究nNOS-PSD复合物与N型钙通道的成簇性及nNOS去磷酸化或磷酸化的酶，并研究这些酶的抑制剂对氮能神经传递的影响。4)探讨糖尿病动物模型（NOD小鼠）抑制性神经传递减少的机制。 公共卫生关系：胃肠动力障碍导致多种疾病，导致吞咽困难、胃灼热、消化不良、便秘和慢性腹痛。这项建议是为了了解这些疾病是如何引起的，以及如何更好地治疗这些疾病可以开发。