Mechanisms underlying regional differences in gastric compliance in the stomach

描述（由申请人提供）：数百万患有功能性消化不良和胃轻瘫的患者（包括特发性和与糖尿病相关的患者）具有餐后胃适应性受损和不协调的胃收缩，其通常伴有腹痛、腹胀和恶心症状。我们的假设是，许多这些胃部疾病是由Cajal间质细胞（ICC）的破坏产生的，这对于：（i）神经介导的收缩和舒张以及（ii）导致在胃的相位区域中观察到的电和机械活动的节律性去极化至关重要。在食物摄入后，近端胃松弛以适应胃容量的增加，而不同时改变胃压力。远端胃通过增加阶段性运动活动来响应胃扩张，这有助于胃内容物的分解和消化。本提案的目的是确定肌内ICC（ICC-IM）在胃底、胃体和胃窦中的特定人群的差异，以及这些差异如何影响胃对进食后扩张的反应方式的区域多样性。一个还原论的方法将进行比较拉伸依赖性反应的组织，分离的肌肉束和新鲜分散的ICC-IM和平滑肌细胞从三个区域不同的胃的差异。将通过检查从动物模型分离的组织来解析ICC-IM的功能作用，所述动物模型在这些区域中的每一个中缺乏ICC-IM并且具有延迟的胃排空，类似于在胃轻瘫患者中观察到的。本提案中概述的实验将提供有关ICC-IM在胃运动活动中的作用以及ICC-IM中离子电导表达差异如何导致胃运动活动区域多样性的重要新信息。本提案中提供的信息对于理解ICC的特定群体如何参与进餐后胃适应或胃壁起搏活动增加以及这些特异性细胞的损失如何导致消化不良或胃轻瘫患者的胃适应受损和胃运动功能障碍至关重要。

DESCRIPTION (provided by applicant): Millions of patients with functional dyspepsia and gastroparesis, both idiopathic and that associated with diabetes mellitus, have impaired postprandial gastric meal accommodation and uncoordinated gastric contractions which are often accompanied with symptoms of abdominal pain, bloating and nausea. Our hypothesis is that many of these gastric disorders are produced by a disruption in interstitial cells of Cajal (ICC) that are critical for: (i) neurally mediated contractions and relaxations and (ii) rhythmic depolarizations that lead to the electrical and mechanical activities observed in the phasic regions of the stomach. Upon food ingestion the proximal stomach relaxes to accommodate increases in gastric volume without concurrent changes in gastric pressure. The distal stomach responds to gastric distension by increasing phasic motor activity that aids in the breakdown and digestion of gastric contents. The objectives of this proposal are to determine the differences in specific populations of intramuscular ICC (ICC-IM) in the fundus, corpus and antrum and how these differences contribute to the regional diversity in the way the stomach responds to distension following ingestion of a meal. A reductionism approach will be undertaken to compare differences in stretch dependent responses in tissues, isolated muscle bundles and freshly dispersed ICC-IM and smooth muscle cells from three regionally distinct areas of the stomach. The functional roles of ICC- IM will be resolved by examining tissues isolated from animal models that lack ICC-IM in each of these regions and have delayed gastric emptying, similar to that observed in gastroparetic patients. Experiments outlined in this proposal will provide important, novel information on the role of ICC-IM in gastric motor actviity and how differences in the expression of ionic conductances in ICC-IM result in regional diversity in gastric motor activity. The information presented in this proposal is critical towards understanding how specific populations of ICC are involved in gastric accomodation or increased pacemaking activity in the stomach wall following meal ingestion and how the loss of these specalized cells could contribute to lead to impaired gastric accomodation and gastric motor dysfunction in patients suffering from dyspepsia or gastroparesis.