Gastroesophageal Antireflux Mechanisms

描述(申请人提供)：胃食道反流病(GERD)影响至少40%的人口。目前治疗GERD的方法并不能防止胃内容物的反流。与GERD相关的问题包括胃灼热对婴儿期吸入性肺炎和成年后食管腺癌的致命并发症的轻微不便。我们对这一建议的中心假设是，胃钩/吊带肌纤维复合体的缺陷是GERD的潜在病因。我们的目标是确定肌肉和神经上的受体，这些肌肉和神经与引起GERD有关。我们的重点是利用这些信息开发针对这些受体的新的药物治疗方法，并对公共卫生和医疗保健支出产生积极影响。目的1：验证GERD患者胃套索/卡环肌纤维复合体的反应与非GERD正常志愿者不同的假设，即这些反应导致返流。我们使用两种不同的方法测量并比较了正常志愿者和GERD患者之间的差异。第一种方法在药物操作前后同时使用高分辨率超声和矢量容量测压，以抑制GEJHPZ的平滑肌成分(阿托品)、增强平滑肌成分(苯儿茶酚)或麻痹骨骼肌成分(顺式阿曲库铵)。第二种方法使用同步内窥镜和胃扩张期间的静态高分辨率测压来确定药物操作前后TLESR的容量和压力扩张阈值。目的：验证完整(Nissen)和270(Touet)胃底折叠术均可通过紧张性M胆碱受体介导的胃底折叠术外膜张力强化有缺陷的吊带/钩状肌纤维复合体，从而减少返流的假说。我们将比较接受这两种手术的GERD患者和接受非食道手术的GERD患者。我们将在手术前、术后1个月和3个月使用有效的GERD问卷和Bravo(R)食道pH监测来评估GERD的程度。对GEJHPZ的评估将使用：1)同时进行高分辨率超声和矢量容量测压，同时进行这种药物操作；2)在胃扩张过程中同时进行内窥镜检查和静态高分辨率测压，以确定TLESR的容量和压力扩张阈值以及GEJHPZ不同组件的打开时间顺序。目的3：验证GERD患者与非GERD患者胃套索/扣带肌纤维复合体收缩性能存在差异的假设。我们比较了来自患有和不患有GERD的器官移植供者的整个胃食道标本的神经递质和受体，这些神经递质和受体负责体外收缩和松弛平滑肌条。我们比较了下列肌条之间的反应：胃套索肌纤维、胃卡环肌纤维、食道下环状肌纤维、食道中部环状肌纤维和纵向食管肌纤维。 公共卫生相关性：胃食道反流影响至少40%的人口。虽然对胃食道反流病(GERD)有有效的症状性酸抑制治疗，但它们并不能防止胃内容物的反流。本研究的目的是明确胃食道高压区的各种成分，特别是胃套索-卡环纤维复合体在GERD发病机制中的作用。

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.