Control of motility in the lower esophageal sphincter

控制下食管括约肌的运动

基本信息

批准号：
10673998
负责人：
Caroline Ann Cobine
金额：
$ 44.01万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673998
关键词：
Achalasia Address Animals Antibodies Barrett Esophagus Biochemical CLCA2 gene Calcium Cells Chest Chronic Complex Coupled Data Defect Deglutition Development Digestion Distal Drug usage Equilibrium Esophagus Food Foundations Functional disorder Future Gene Expression Generations Genetic Giant Cells Human Hypotensives Image Immunohistochemistry Inferior esophageal sphincter structure Inflammatory Ingestion Interstitial Cell of Cajal Investigation Label Macaca Macaca fascicularis Maintenance Measurement Mediating Medical Metabolic Molecular Monitor Mucous Membrane Mus Muscle Neurons Nitric Oxide Nitroxidergic Nerves Nutrient Outcome Pain Paper Pathway interactions Patients Phosphorylation Physiological Primates Principal Investigator Probability Process Reflex action Reflux Regulation Relaxation Resolution Respiratory Diaphragm Respiratory System Role Smooth Muscle Myocytes Stomach Stomach Content Structure Techniques Transgenic Mice aspirate carcinogenesis cell motility experience experimental study interstitial cell motility disorder mouse model neural neuroregulation neurotransmission new therapeutic target novel novel therapeutics optogenetics oxidative DNA damage preclinical study prevent programs protein expression response voltage ward

项目摘要

Program Director/Principal Investigator (Last, First, Middle): Cobine, Caroline, A Project Summary The lower esophageal sphincter (LES) is a thickened region of muscle between the distal esophagus and proximal stomach. The LES develops contractile tone that forms a protective barrier and restricts acidic contents of the stomach from being refluxed into and damaging the esophagus. LES tone is thought to be ‘myogenic’, but LES muscles are not just composed of smooth muscle cells (SMCs) and neurons. Rather, interstitial cells of Cajal (ICC) are electrically coupled to SMCs and regulate the excitability of SMCs. For example, we found that responses to nitrergic input, an important regulator of relaxation after swallowing, are reduced in animals with loss of ICC (W/WV mice). This concept was criticized because manometric measurements in W/WV mice displayed evidence of nitrergic relaxation. An important observation in these studies, but not investigated or discussed in terms of mechanism, was that the LES in W/WV mice is hypotensive, suggesting that ICC provide important functions in the LES, such as development and maintenance of tone. This project seeks to better understand the mechanism of LES tone. Preliminary findings suggest that activation of Ca2+-dependent Cl- channels (CaCC encoded by Ano1), most highly expressed by ICC in the LES, are responsible for a significant portion of tone in these muscles. Ano1 channels are activated by spontaneous Ca2+ transients in ICC. The inward current activated by Ca2+ causes depolarization of the syncytium and increases the open probability of voltage-dependent Ca2+ channels in SMCs. The degree of contraction by this mechanism appears also to be regulated by a mechanism known as Ca2+ sensitization, a process suggested in previous papers, but previous findings are subject to other explanations. Here we propose to investigate the following: 1. Determine the molecular and functional apparatus responsible for the electromechanical and pharmacomechanical regulation of tone in the LES, 2. Examine how inputs from intrinsic neurons modulate the electromechanical and pharmacomechanical mechanisms underlying LES tone. This study will utilize a variety of cutting-edge techniques, such as transgenic mice, optogenetic monitoring of Ca2+ transients and biochemical analysis of phosphorylation steps that either increase or inhibit Ca2+ sensitivity in SMCs. Many of these pre-clinical studies will be performed on mice, but we will also perform parallel studies on Cynomolgus monkey LES, a primate with significant genetic homology to humans. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

项目总监/首席研究员（最后，第一，中间）：Cobine，Caroline，A 项目摘要食管下部括约肌（LES）是食管远端和近端stallach。 LE形成收缩色调，形成受保护的屏障并限制酸性含量摊位从反射和破坏食道。 Les音调被认为是“肌原性的”，但是LES肌肉不仅由平滑肌细胞（SMC）和神经元组成。而是，间质细胞 Cajal（ICC）电与SMC进行电耦合并调节SMC的兴奋。例如，我们发现对氮气输入的反应是吞咽后的重要放松调节剂，在具有的动物中减少 ICC的损失（W/WV小鼠）。这个概念至关重要，因为W/WV小鼠的测量测量值显示了硝化松弛的证据。这些研究中的一个重要观察结果，但未研究或根据机制讨论的是，W/WV小鼠中的LE是降低的，这表明ICC提供了 LE的重要功能，例如开发和维护语调。这个项目试图更好了解LES音调的机制。初步发现表明，Ca2+依赖性Cl-的激活 ICC在LES中最高表达的通道（由ANO1编码的CACC）是重要的这些肌肉中的音调一部分。 ANO1通道通过ICC中的赞助Ca2+瞬变激活。这由Ca2+激活的内向电流导致合胞体沉积，并增加 SMC中的电压依赖性Ca2+通道。通过这种机制的收缩程度似乎也是由称为Ca2+灵敏度的机制调节，这是先前论文中建议的过程，但以前调查结果受其他解释的约束。在这里，我们建议研究以下内容：1。确定负责机电和药理调节的分子和功能设备 LES中的音调，2。检查固有神经元的输入如何调节机电和 LES音调的基础药物机制。这项研究将利用各种尖端技术，例如转基因小鼠，CA2+瞬态的光遗传学监测以及生化分析磷酸化步骤增加或抑制SMC中Ca2+灵敏度。这些临床前研究中的许多将在小鼠上进行，但我们还将对Cynomolgus Monkey Les进行平行研究，该研究与人类的重要遗传同源性。 OMB No. 0925-0001/0002（Rev. 03/2020通过02/28/2023批准）页面延续格式页面