Gastroesophageal Antireflux Mechanisms

描述（由申请人提供）：胃食管反流病（GERD）影响至少40%的人群。目前GERD的治疗不能防止胃内容物的反流。与GERD相关的问题包括胃灼热的轻微不便，婴儿期吸入性肺炎和成年期食管腺癌的致命并发症。我们的中心假设是，胃扣/吊索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上的受体和神经支配这些肌肉，涉及引起胃食管反流病。我们的重点是利用这些信息开发针对这些受体的新的药理学治疗方法，并对公共卫生和医疗保健支出产生积极影响。 目标1：检验GERD患者与无GERD的正常志愿者相比，胃吊带/钩状肌纤维复合体的反应不同且这些反应导致反流的假设。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。第一种方法在药理学操作之前和之后使用同步高分辨率超声检查和向量容积测压法，以抑制GEJHPZ的平滑肌成分（阿托品），增加平滑肌成分（氨甲酰胆碱）或麻痹骨骼肌成分（顺氯氨丁氨）。第二种方法在胃扩张期间同时使用内窥镜检查和固定高分辨率测压，以确定这种药理学操作前后TLESR的体积和压力扩张阈值。 目标二：检验完整（Nissen）和270：（Toupet）胃底折叠术均通过增强胃底折叠术包裹物中的张力性毒蕈碱受体介导的胃平滑肌张力来加强有缺陷的悬带/钩肌纤维复合体，从而减少反流的假设。我们将比较接受这2种手术的GERD患者与接受非食管手术的无GERD患者。我们将在术前和术后1个月和3个月使用经验证的GERD问卷和Bravo（R）食管pH监测评估GERD程度。将使用以下方法评价GEJHPZ：1）同时进行高分辨率超声检查和向量容积测压（采用该药理学操作）和2）在胃扩张期间同时进行内镜检查和固定高分辨率测压，以确定TLESR的容积和压力扩张阈值以及GEJHPZ各组成部分打开的时间顺序。 目标3：检验有和无GERD的受试者之间胃吊带/钩肌纤维复合体收缩力存在差异的假设。我们比较了神经递质和受体负责在体外收缩和松弛的平滑肌条从整个胃食管标本获得器官移植捐赠者和不GERD。我们比较以下肌条之间的反应：胃吊索肌纤维，胃扣肌纤维，下食管环形肌纤维，中食管环形肌纤维，和纵向食管肌纤维。 公共卫生相关性：胃食管反流影响至少40%的人口。虽然胃食管反流病（GERD）的有效对症抑酸治疗是可用的，但它们不能防止胃内容物的反流。该建议的目的是确定胃食管高压区的各种成分，特别是胃吊索-扣纤维复合体在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.