Gastroesophageal Antireflux Mechanisms

胃食管抗反流机制

• 批准号: 8332412
• 负责人: LARRY S MILLER
• 金额: $ 6.29万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332412
• 关键词: Acids; Adult; Affect; Atropine; Bethanechol; Complex; Defect; Disease; Distal; Donor person; Endoscopy; Esophageal; Esophageal Adenocarcinoma; Esophagus; Etiology; Fiber; Functional disorder; Fundoplication; Gastroesophageal reflux disease; Goals; Health Expenditures; Heartburn; In Vitro; Inferior esophageal sphincter structure; Liquid substance; Manometry; Measures; Mediating; Minor; Monitor; Muscarinic Acetylcholine Receptor; Muscle; Muscle Fibers; Natural History; Nerve; Neurotransmitter Receptor; Operative Surgical Procedures; Organ Transplantation; Paralysed; Pathogenesis; Patients; Physiological; Pneumonia; Population; Procedures; Public Health; Questionnaires; Randomized; Reflux; Relaxation; Resolution; Respiratory Diaphragm; Role; Skeletal Muscle; Smooth Muscle; Specimen; Stomach; Testing; Ultrasonography; infancy; innovation; novel; pressure; prevent; public health priorities; public health relevance; receptor; response; treatment strategy; vector; volunteer

DESCRIPTION (provided by applicant): Gastro esophageal reflux disease (GERD) affects at least 40% of the population. Current treatments for GERD do not prevent reflux of gastric contents. Problems associated with GERD include the minor inconveniences of heartburn to the lethal complications of aspirational pneumonia in infancy and esophageal adenocarcinoma in adulthood. Our central hypothesis of this proposal is that a defect in the gastric clasp/sling muscle fiber complex is the underlying etiology of GERD. Our objectives are to identify receptors on the muscles and the nerves innervating these muscles that are implicated as causing GERD. Our focus is to use this information to develop new pharmacologic treatments targeting these receptors and impacting positively on the public health and health care expenditures. Aim 1: Test the hypothesis that GERD patients have different responses of the gastric sling/clasp muscle fiber complex than normal volunteers without GERD and that these responses result in reflux. We measure and compare differences between normal volunteers and GERD patients using two different approaches. The first approach uses simultaneous high-resolution ultrasonography and vector volume manometry before and after pharmacologic manipulation to inhibit the smooth muscle component (atropine) augment the smooth muscle component (bethanechol) or paralyze the skeletal muscle component (cisatracurium) of the GEJHPZ. The second approach uses simultaneous endoscopy and stationary high resolution manometry during gastric distension to determine the volume and pressure distension threshold for TLESRs before and after this pharmacologic manipulation. Aim 2: Test the hypothesis that both complete (Nissen) and 270: (Toupet) fundoplication procedures reduce reflux by strengthening the defective sling/clasp muscle fiber complex through tonic muscarinic receptor mediated tension of the gastric smooth muscle in the wrap of the fundoplication. We will compare GERD patients undergoing these 2 procedures to patients without GERD undergoing non-esophageal surgery. We will evaluate degree of GERD using both validated GERD questionnaires and Bravo(R) esophageal pH monitoring before surgery and at 1 and 3 months post operatively. GEJHPZ will be evaluated using: 1) simultaneous high-resolution ultrasonography and vector volume manometry with this pharmacologic manipulation and 2) simultaneous endoscopy and stationary high resolution manometry during gastric distension to determine volume and pressure distension threshold for TLESRs and temporal sequence of opening of the various components of the GEJHPZ. Aim 3: Test the hypothesis that there is a difference in contractility of the gastric sling/clasp muscle fiber complex between subjects with and without GERD. We compare the neurotransmitters and receptors responsible for in-vitro contraction and relaxation of smooth muscle strips from whole gastro esophageal specimens obtained from organ transplant donors with and without GERD. We compare responses between the following muscle strips: gastric sling muscle fibers, gastric clasp muscle fibers, lower esophageal circular muscle fibers, mid esophageal circular muscle fibers, and longitudinal esophageal muscle fibers. PUBLIC HEALTH RELEVANCE: Gastro esophageal reflux affects at least 40% of the population. Although effective symptomatic acid suppressive treatments for gastroesophageal reflux disease (GERD) are available, they do not prevent reflux of gastric contents. The goal of this proposal is to define the role of the various components of the gastroesophageal high-pressure zone, in particular the gastric sling-clasp fiber complex, in the pathogenesis of GERD.

描述（由申请人提供）：胃食管反流疾病（GERD）至少影响40％的人口。当前对GERD的处理不能阻止胃含量的回流。与GERD相关的问题包括对婴儿期和食管腺癌的胃灼热的轻微不便。我们对该提案的中心假设是胃扣/吊带肌纤维复合物的缺陷是GERD的基本病因。我们的目标是识别肌肉上的受体和神经支配这些肌肉的神经，这些肌肉与引起gerd有关。我们的重点是使用这些信息来开发针对这些受体并对公共卫生和医疗保健支出产生积极影响的新药理治疗。 AIM 1：检验以下假设：GERD患者与没有GERD的正常志愿者的胃吊带/扣肌纤维纤维复合物的反应不同，并且这些反应会导致反流。我们使用两种不同的方法测量和比较正常志愿者和GERD患者之间的差异。第一种方法使用同时的高分辨率超声检查和药理学操纵前后的矢量体积测量法来抑制平滑肌成分（阿托罗金）增强平滑肌成分（伯特氏菌）或使骨骼肌成分（Cisatracrium）（Cisatracrium）（Cisatracrium）抑制Gejhpz的骨骼肌肉成分。第二种方法在胃扩张期间使用同时内窥镜检查和固定高分辨率测量法，以确定该药物操纵前后TLESR的体积和压力延伸阈值。 目标2：检验完整（Nissen）和270的假设：（Toupet）底基折叠程序通过通过强直毒素受体介导的胃平滑肌的张力来增强缺陷的吊带/扣子肌纤维纤维复合物，从而减少反流，从而减少反流。我们将将接受这两种手术的GERD患者与没有GERD进行非食道手术的患者进行比较。我们将使用经过验证的GERD问卷和Bravo（R）食管pH监测在手术前和手术后1和3个月时评估GERD程度。 GEJHPZ将使用：1）通过这种药理操作以及2）同时进行高分辨率的超声检查和矢量体积测量，以及2）同时进行胃扩张期间的内窥镜检查和固定的高分辨率测压，以确定tlesrs和gejhpz的tlesrs and Perimal overal of gejhpz的量和压力扩张阈值。 AIM 3：检验以下假设：胃吊带/扣肌纤维纤维复合物的收缩力有所不同。我们比较了负责体外收缩的神经递质和受体，以及从有或没有GERD的器官移植供体获得的整个胃食管样本中的平滑肌条放松。我们比较以下肌肉条之间的反应：胃吊带肌纤维，胃扣肌纤维，较低的食管圆形肌肉纤维，中食管中食管圆形肌肉纤维和纵向食管肌纤维。 公共卫生相关性：胃食管反流至少40％的人口。尽管有效的有症状酸抑制性胃食管反流疾病（GERD）可用，但它们并不能阻止胃含量的回流。该提案的目的是定义胃食管反应区的各种成分的作用，尤其是胃吊带式纤维纤维复合物在GERD的发病机理中的作用。