COBRE: UNV MED SCH: P4: REMODELING OF NEUROMUSCULAR CONTROL IN GI SMOOTH MUSCLE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 胃肠道内容物的移动是由肌层的收缩和松弛引起的。这些收缩推动腔内容物沿胃肠道从口到胎的方向。当出现部分管腔阻塞，从而影响内容物的正常流动时， 肠道功能不正常。在对肠梗阻的反应中，最显著的变化之一是单个平滑肌细胞的数量和大小急剧增加和显著的 肠神经细胞增大。尽管肥大在胃肠道组织中普遍存在，并且发生了结构变化，但这种对增加的功能需求的反应以及在这一过程中发生的生理变化的机制还很不清楚。这种缺乏了解的部分原因可能是未能采用最先进的综合技术来检查这一问题。这项提案中描述的新技术将为研究结肠肥大引起的病理生理变化的潜在机制提供前所未有的见解。这些技术将包括膜片钳和细胞内微电极记录、钙成像、免疫组织化学、神经递质释放研究、单细胞RT-PCR和蛋白质组学方法。我们将确定神经-神经元和神经肌肉传递通路中的哪些元素受到结肠肥大的影响。在肥大过程中发生的生理变化将用表现为结肠肥大的突变小鼠和由部分结肠梗阻引起的小鼠进行检测。这项研究还将首次全面分析特定类型的肠神经元的神经元回路和化学编码的肥大变化。此外，这些研究将确定在结肠肥大恢复后，平滑肌是否显示出可塑性并能够恢复到原来的状态。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The movement of luminal contents along the gastrointestinal (GI) tract is generated by contractions and relaxations of the tunica muscularis. These contractions propel luminal contents in an oral to aboral direction along the GI tract. When a partial luminal obstruction occurs, which impairs the normal flow of contents, the bowel ceases to function properly. One of the most pronounced changes that occur in response to bowel obstruction is the dramatic increase in the number and size of individual smooth muscle cells and a marked enlargement of enteric neurons. Despite the prevalence of hypertrophy in GI tissues and the well documented structural changes that occur, the mechanisms underlying this response to increased functional demands and the physiological changes that occur during this process are very poorly defined. This lack of understanding may in part be attributable to the failure to employ state of the art integrative technologies to examine this problem. The novel techniques described in this proposal will provide an unprecedented insight into the mechanisms underlying the pathophysiological changes that occur in response to colonic hypertrophy. These techniques will include patch clamp and intracellular microelectrode recordings, calcium imaging, immunohistochemistry, neurotransmitter release studies, single cell RT-PCR and a proteomics approach. We will determine which elements of the neuro-neuronal and neuromuscular transmission pathways are affected by colonic hypertrophy. The physiological changes that occur during hypertrophy will be examined using mutant mice which exhibit colonic hypertrophy and mice in which hypertrophy is induced by a partial obstruction of the colon. This study will also provide the first comprehensive analysis of the hypertrophic changes in the neuronal circuits and chemical coding of specific classes of enteric neurons. In addition, these studies will determine if smooth muscle displays plasticity and can revert to its original state following recovery from colonic hypertrophy.