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.
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