Neuronal Excitability and Motility in Colitis

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DESCRIPTION (provided by applicant): Intestinal inflammation leads to changes in a variety of functions, including motility, secretion and sensitivity. Neural circuits of the bowel regulate ll of these functions, and it is likely that changes in these reflex circuits contribute to the symptos suffered by afflicted individuals. In the past 8 years, we have evaluated inflammation-induced changes along the circuitry of the colon in a step-wise fashion, and we have identified fundamental changes at several sites, including: (1) increased serotonin availability in the mucosal layer; (2) intrinsic sensory neuron hyperexcitability; (3) facilitation of synaptic signals between neurons; and (4) attenuated inhibitory purinergic neuromuscular transmission. Furthermore, we have elucidated the mechanisms that underlie many of these changes, determined what changes persist following recovery from inflammation, and linked changed in neural function to altered motility patterns. In this grant application, we are proposing to build upon our findings and those of others to examine novel mechanisms by which gut functions and bone density can be affected by inflammation, and explore innovative approaches to prevent or reverse these changes and to minimize mucosal damage during the inflammatory response. The first aim of this grant application is designed to test the hypothesis that the inflammation- induced decrease in purinergic neuromuscular transmission involves a decrease in purine synthesis and release as the result of oxidative stress damage to mitochondria in the muscular is of the inflamed colon. Experiments proposed in the second aim is based on our recent discovery that 5-HT4 receptors (5HT4Rs) are highly expressed in the colonic epithelium, and that activation of these receptors induces 5-HT, mucus, and Cl- secretion, and promotes propulsive motility. We will test the hypothesis that activation of 5-HT4Rs on cells in the epithelial lining has a protective effect, attenuating the severity of colitis and protecting colonc motor function. Specific aim 3 is based on the knowledge that various forms of intestinal inflammation are associated with decreased bone density, and the recent discovery that circulating gut-derived serotonin has a negative impact on bone formation. We will test the hypothesis that the inflammation-induced increase in mucosal serotonin availability contributes to the decrease in bone density, and that these effects can be reduced by modulating mucosal serotonin signaling or by inhibiting the 5-HT1B receptor, which is expressed by pro-osteoblasts. This proposal involves an integrated approach, using state-of-the-art techniques, to investigate novel concepts related to the neuromuscular and serotonin signaling in the gut, and to examine a potential damaging relationship between mucosal serotonin and bone integrity. The findings of these studies will greatly improve our understanding of purinergic neuromuscular transmission and mucosal serotonin signaling in the gut.