Mechanisms underlying regional differences in gastric compliance in the stomach.

描述(申请人提供)：数以百万计的功能性消化不良和胃轻瘫患者，包括特发性和与糖尿病相关的患者，餐后胃餐调节功能受损，胃收缩不协调，经常伴随腹痛、腹胀和恶心的症状。我们的假设是，许多这些胃病是由Cajal间质细胞(ICC)的破坏引起的，ICC对：(I)神经介导的收缩和松弛以及(Ii)导致胃相区观察到的电和机械活动的节律性去极化至关重要。进食后，近端胃放松，以适应胃容量的增加，而不会同时改变胃压力。远端胃对胃扩张的反应是通过增加时相运动活动来帮助胃内容物的分解和消化。本研究的目的是确定胃底、胃体和胃窦部肌内ICC(ICC-IM)的特定群体的差异，以及这些差异如何导致胃对进食后膨胀的反应方式的区域差异。将采用一种简化论的方法来比较组织、分离的肌束和新分散的ICC-IM以及来自胃的三个不同区域的平滑肌细胞中拉伸依赖反应的差异。ICC-IM的功能作用将通过检测从动物模型中分离出来的组织来解决，这些动物模型中的每个区域都缺乏ICC-IM，并具有胃排空延迟，类似于在胃瘫患者中观察到的组织。本提案中概述的实验将为ICC-IM在胃运动中的作用以及ICC-IM中离子电导的表达差异如何导致胃运动活动的区域差异提供重要的新信息。这项建议中提供的信息对于了解特定的ICC群体如何参与进食后胃调节或胃壁起搏活动增加以及这些特殊细胞的丧失如何导致消化不良或胃瘫患者的胃调节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.