权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Identification and activation mechanisms of vagal and spinal nociceptors in esophageal mucosa

食管粘膜迷走神经和脊髓伤害感受器的识别和激活机制

基本信息

批准号：
9978776
负责人：
Thomas Edward Taylor-Clark
金额：
$ 35.24万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-25 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978776
关键词：
ASIC channel Acids Address Anatomy Animal Model Animals Bile Acids C Fiber Cations Cavia Chest Pain Clinical Data Development Electrophysiology (science)Embryo Esophageal mucous membrane Esophagus Esthesia Failure Family Fiber Functional disorder Future GPBAR1 gene Gastric Acid Gastroesophageal reflux disease Gene Expression Profiling Gene Silencing Genes Genetic Green Fluorescent Proteins Health Heartburn Human Investigation Knowledge Lead Location Mediating Medical Methods Molecular Mucous Membrane Nerve Nerve Fibers Neural Crest Neurons Neurotransmitters Nociception Nociceptors Organ Donor Pain Paper Patients Pharmaceutical Preparations Pharmacology Population Positioning Attribute Potassium Process Proton Pump Inhibitors Protons Publishing Reflex action Reflux Refractory Spinal Stomach Content Symptoms TRPV1 gene Target Populations Therapeutic Tissues United States afferent nerve base differential expression experience in vivo knock-down multiphoton imaging neuroregulation novel pain sensation patch clamp patient population persistent symptom receptor response small hairpin RNA targeted treatment transgene expression

项目摘要

Project Summary Gastroesophageal reflux disease (GERD) is a major health problem in the United States, impacting over 20% of the population. In at least a quarter of these patients, symptoms caused by GERD such as heartburn and chest pain cannot be controlled by gastric acid suppression with proton pumps inhibitors (PPIs). This population of patients with PPI-refractory GERD have no effective medical treatment options. Failure to understand mechanisms of persistent symptoms in this condition is a major knowledge gap, and limits clinical therapeutic options. One potential cause of persistent symptoms in PPI-refractory GERD patients is weakly acidic (pH>5.0) reflux. This can cause activation of pain- mediating nerves (C-fiber nociceptors) in esophageal mucosa, but the molecular mechanisms have not been clearly elucidated. Furthermore it is not clear whether bile acid also directly activates esophageal C-fibers and mediates nociceptive symptoms in GERD. Our overall hypothesis is that the refluxates in PPI-refractory GERD (mild acid and bile acids) activate esophageal nociceptive C-fiber subtypes and contribute to persistent symptoms in refractory GERD. Determining the identity of the afferent nerve subtype(s) and the key receptor(s) responsible for PPI refractory symptoms are crucial for development of specific targets for this population. Over the past decade, we have identified 3 types of C-fibers in the esophagus which express differential receptors and neurotransmitters and have different central projections. Intriguingly, we have developed new data which demonstrated that two factors in weakly acidic refluxate robustly stimulate esophageal C-fibers: 1) bile acids (that are quite often found in the refluxates on PPI therapy), and 2) acid in low proton concentrations (pH=6.0, termed here mild acid). Our published papers and preliminary data suggest that the key receptors TGR5 and TASK1/ASIC3 are likely involved. Based on these progresses, we will first determine in aim 1 the subtypes of nociceptive afferent nerve terminals in esophagus mucosa which are more vulnerable to refluxates. We will then elucidate receptors mediating C-fiber activation by mild acid in aim 2. We will address the hypothesis that mild acid activates C-fiber subtypes via combination of inhibition of potassium two-pore domain (K2P) family channel (TASK1) and activation of cationic channels from the ASIC family (ASIC3). In aim 3, we will elucidate receptors mediating C-fiber activation by bile acids. We hypothesize that bile acids activate C- fiber subtype(s), which is mediated by the bile acid receptor TGR5. We will apply the approaches of gene expression analysis, patch clamp recordings, and recordings of nerve activity originating in the C-fiber nerve terminals. Studies will be carried out in in animal models in which neuron-selective gene knockdown by our validated in vivo shRNA silencing strategy. Elucidation of the mechanisms by which bile acids and mild acid activate C-fibers will help to develop novel targets for PPI--refractory GERD.

项目摘要胃食管反流病（GERD）是美国的一个主要健康问题， 20%的人口。在至少四分之一的这些患者中，由GERD引起的症状，如胃灼热和胸痛不能通过质子泵抑制剂抑制胃酸来控制（PPI）。该PPI难治性GERD患者人群未接受有效的药物治疗选项.不了解这种情况下持续症状的机制是一个主要的问题。知识差距，限制了临床治疗选择。持续症状的一个潜在原因 PPI难治性GERD患者为弱酸性（pH>5.0）反流。会引起疼痛- 介导神经（C-纤维伤害感受器）在食管粘膜，但分子机制还没有已明确阐明。此外，尚不清楚胆汁酸是否也直接激活食管癌。 C-纤维和介导GERD的伤害性症状。我们的总体假设是， PPI难治性GERD（弱酸和胆汁酸）激活食管伤害性C纤维亚型，导致难治性GERD的持续症状。确定传入神经的身份亚型和负责PPI难治性症状的关键受体对发展至关重要针对这一人群的具体目标。在过去的十年中，我们已经确定了3种类型的C-纤维在食管表达不同受体和神经递质，具有不同的中枢神经系统，预测。有趣的是，我们已经开发了新的数据，表明两个因素在弱酸性反流强烈刺激食管C-纤维：1）胆汁酸（其经常在食管中发现）， PPI治疗的反流），和2）低质子浓度的酸（pH=6.0，在此称为弱酸）。我们已发表的论文和初步数据表明，关键受体TGR 5和TASK 1/ASIC 3可能是涉案在此基础上，我们将首先在目标1中确定伤害性传入神经的亚型食管粘膜中的神经末梢更容易受到反流的影响。然后我们将阐明受体介导的C-纤维激活的弱酸在目的2。我们将讨论弱酸通过抑制钾双孔结构域（K2 P）家族的组合激活C-纤维亚型通道（TASK 1）和ASIC家族的阳离子通道（ASIC 3）的激活。在目标3中，我们阐明受体介导的C-纤维激活胆汁酸。我们假设胆汁酸激活C- 纤维亚型，其由胆汁酸受体TGR 5介导。我们将应用基因的方法表达分析、膜片钳记录和起源于C纤维的神经活动记录神经末梢研究将在动物模型中进行，其中神经元选择性基因通过我们验证的体内shRNA沉默策略敲减。阐明其机制，胆汁酸和弱酸激活C纤维将有助于开发PPI难治性GERD的新靶点。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acidic Pharyngeal Reflux Does Not Correlate with Symptoms and Laryngeal Injury Attributed to Laryngopharyngeal Reflux.

酸性咽部反流与症状和喉损伤无关。

DOI：
10.1007/s10620-018-5372-1
发表时间：
2019-05
期刊：
DIGESTIVE DISEASES AND SCIENCES
影响因子：
3.1
作者：
Duricek, Martin;Banovcin, Peter;Halickova, Tatiana;Hyrdel, Rudolf;Kollarik, Marian
通讯作者：
Kollarik, Marian

Comprehensive analysis of acidic pharyngeal reflux before and after proton pump inhibitor treatment in patients with suspected laryngopharyngeal reflux.

质子泵抑制剂治疗前后对可疑喉咽反流的患者进行酸性咽部反流的全面分析。

DOI：
10.1097/meg.0000000000001584
发表时间：
2020-02
期刊：
EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY
影响因子：
2.1
作者：
Duricek, Martin;Banovcin, Peter, Jr.;Halickova, Tatiana;Hyrdel, Rudolf;Kollarik, Marian
通讯作者：
Kollarik, Marian

Structure of vagal afferent nerve terminal fibers in the mouse trachea.

DOI：
10.1016/j.resp.2018.01.001
发表时间：
2018-03
期刊：
Respiratory physiology & neurobiology
影响因子：
2.3
作者：
Hennel M;Harsanyiova J;Ru F;Zatko T;Brozmanova M;Trancikova A;Tatar M;Kollarik M
通讯作者：
Kollarik M

Mapping of the Sensory Innervation of the Mouse Lung by Specific Vagal and Dorsal Root Ganglion Neuronal Subsets.

通过特定迷走神经和背根神经节神经元亚群绘制小鼠肺的感觉神经支配图。

DOI：
10.1523/eneuro.0026-22.2022
发表时间：
2022
期刊：
eNeuro
影响因子：
3.4
作者：
Kim,Seol-Hee;Patil,MayurJ;Hadley,StephenH;Bahia,ParmvirK;Butler,ShaneG;Madaram,Meghana;Taylor-Clark,ThomasE
通讯作者：
Taylor-Clark,ThomasE

Vagus Nerves Provide a Robust Afferent Innervation of the Mucosa Throughout the Body of the Esophagus in the Mouse.