Role of clock genes in colonic motility

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DESCRIPTION (provided by applicant): Humans have bowel movements during the day, frequently following awakening or following a meal but rarely during the night. In line with this observation are ambulatory pressure recordings demonstrating maximal colonic activity during the day. Thus colonic motility follows a rhythm. Disruption of our daily rhythm such as occurs with shift work or time zone traveling, is associated with gastrointestinal symptoms. These observations suggest a functional correlation between our daily rhythm and gastrointestinal physiology. Biological rhythms are controlled by clock genes. A central clock is located in the brain. However, clock genes are present in peripheral organs as well. Within peripheral organs, clock genes control the expression of a subset of tissue-specific genes, thereby directly affecting physiological function. Clock genes can synchronize themselves to external time cues such as the light/dark cycle and feeding. Our preliminary data show expression of clock genes in the murine colon. This expression is rhythmic and increases at the start of the dark cycle. Along with this, enzymes involved in the synthesis of the colonic neurotransmitters acetylcholine and nitric oxide increase at the onset of the dark cycle. Moreover, we show that mice pass an increased number of stool pellets at night. This is associated with increased nocturnal intracolonic pressure activity, as assessed by a newly developed method for prolonged intracolonic pressure monitoring in freely moving mice. We show colonic clock gene expression in the myenteric plexus, an important site of neurotransmitter synthesis. Taken together, the data suggest that the colon may have a time-keeping capability that allows for the physiological adaptation of colonic motility to environmental stimuli. We hypothesize that changes in the light/dark cycle and feeding schedule affect colonic motility through clock genes. The overall goal of our studies are to determine the effect of changes in light/dark cycle and feeding schedule on clock gene expression, neurotransmitter synthesizing enzyme expression and colonic motility in wildtype and clock gene (PER1/PER2) knockout mice. To this extent we will use laser capture microscopy, real-time PCR and colonic motility studies. This proposal will establish whether clock genes play a role in colonic motility. This is important, as gastrointestinal dysfunction is a common complaint of time-zone travelers and shift workers. We speculate that the gastrointestinal symptoms of those individuals result from the inability of clock genes to make timely adjustments to changes in environmental cues. The long-term goal for this project is to develop a better understanding of the role of clock genes in colonic motility, the pathways participating in the entrainment of colonic clock genes, their role in dysmotility syndromes and eventually, the development of pharmacological interventions that will enhance the synchronization of clock genes to changes in the environment.