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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 腔内容物沿着胃肠（GI）道的运动由图尼卡肌层的收缩和舒张产生。这些收缩将腔内容物沿胃肠道从口腔向反口腔方向沿着推进。当发生部分管腔阻塞时，其损害内容物的正常流动， 肠道停止正常运作。肠梗阻时发生的最显著变化之一是单个平滑肌细胞的数量和大小急剧增加， 肠神经元增大。尽管胃肠道组织中肥大的流行和发生的结构变化有充分的记录，但对增加的功能需求和在此过程中发生的生理变化的反应机制的定义非常差。这种缺乏理解的部分原因可能是未能采用最先进的综合技术来研究这个问题。本提案中描述的新技术将提供一个前所未有的洞察机制的病理生理变化，发生在结肠肥大。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。将使用表现出结肠肥大的突变小鼠和结肠部分梗阻诱导肥大的小鼠检查肥大期间发生的生理变化。这项研究还将提供第一个全面的分析，在神经元回路和化学编码的特定类别的肠神经元的肥大变化。此外，这些研究将确定平滑肌是否表现出可塑性，并在从结肠肥大恢复后恢复到其原始状态。

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.