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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。管腔内内容物沿胃肠道的运动是由肌膜的收缩和松弛产生的。这些收缩推动腔内内容物沿胃肠道由口向腹的方向移动。当部分肠管梗阻发生时，就会妨碍肠内内容物的正常流动，肠便停止正常运作。肠梗阻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，肠神经元明显增大。尽管肥大在胃肠道组织中普遍存在，并且发生的结构变化也有很好的记录，但这种对功能需求增加的反应的机制以及在此过程中发生的生理变化却知之甚少。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。本提案中描述的新技术将提供前所未有的深入了解结肠肥大病理生理变化的机制。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。我们将确定哪些神经神经元和神经肌肉传递途径的元素受到结肠肥大的影响。在肥厚过程中发生的生理变化将用表现结肠肥厚的突变小鼠和由部分结肠梗阻引起肥厚的小鼠进行检查。这项研究还将首次全面分析神经元回路的肥厚变化和特定类别肠神经元的化学编码。此外，这些研究将确定平滑肌是否表现出可塑性，并在结肠肥大恢复后恢复到原来的状态。

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.