Gastroesophageal Antireflux Mechanisms

描述（由申请人提供）：胃食管反流病（GERD）影响至少40%的人口。目前治疗胃反流的方法不能防止胃内容物反流。与胃食管反流相关的问题包括轻微的胃灼热、婴儿期吸入性肺炎和成年期食管腺癌等致命并发症。我们的中心假设是胃环/胃吊带肌纤维复合物的缺陷是胃反流的潜在病因。我们的目的是确定肌肉上的受体和支配这些肌肉的神经与引起胃食管反流有关。我们的重点是利用这些信息来开发针对这些受体的新药物治疗，并对公共卫生和卫生保健支出产生积极影响。目的1：验证GERD患者对胃吊带/胃扣肌纤维复合物的反应与没有GERD的正常志愿者不同的假设，这些反应导致反流。我们使用两种不同的方法测量和比较正常志愿者和胃食管反流病患者之间的差异。第一种方法是在药理学操作前后同时使用高分辨率超声检查和矢量体积压力测量来抑制GEJHPZ的平滑肌成分（阿托品），增强平滑肌成分（乙二酚）或麻痹骨骼肌成分（顺阿曲库铵）。第二种方法是在胃膨胀期间同时使用内窥镜和固定式高分辨率测压仪来确定tlesr在这种药物操作前后的体积和压力膨胀阈值。目的2：验证完整（Nissen）和270:（Toupet）底叠手术通过强直性毒碱受体介导的胃平滑肌在底叠膜上的张力，通过加强有缺陷的吊带/扣型肌纤维复合体来减少反流的假设。我们将比较接受这两种手术的胃食管反流患者和没有接受非食管手术的胃食管反流患者。我们将在手术前和术后1个月和3个月使用经验证的GERD问卷和Bravo(R)食管pH监测来评估GERD的程度。GEJHPZ将通过以下方法进行评估：1)同时进行高分辨率超声检查和矢量容积测压，采用这种药理学操作；2)胃膨胀期间同时进行内窥镜检查和固定式高分辨率测压，以确定tlesr的容积和压力膨胀阈值以及GEJHPZ各组成部分打开的时间顺序。目的3：检验胃吊带/胃扣肌纤维复合体在有和没有胃反流的受试者之间的收缩性差异的假设。我们比较了来自器官移植供体的全胃食管标本中负责体外收缩和松弛的神经递质和受体，这些标本来自有和没有胃食管反流的器官供体。我们比较了以下肌肉条的反应：胃吊带肌纤维、胃扣肌纤维、食管下袢肌纤维、食管中袢肌纤维和食管纵向肌纤维。

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.