Grant: $99,992 - National Institutes of Health - Aug. 20, 2009
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Award Description: In humans, abnormal colonic motor patterns have been implicated in the pathogenesis of severe transit constipation (STC) and diarrhea (Bueno et al., 1980). STC has been attributed to many factors including: an increase in NOS positive neurons within the gut wall, an excess production of nitric oxide (NO), a decrease in NK2 receptors, a reduction in the responses to acetylcholine, an increased inhibitory response to the muscle, reductions in muscle tone and contractile activity, reduced peristalsis, reductions in ICC, increased absorption or decreased secretion and hypoganglionosis (Bassoti et al., 1999; Cortesini et al., 1995; Knowles, Martin, 2000; Lee et al., 2005; Stanton et al., 2003; Tomita, Howard, 2008; Tomita et al., 2002; Watchow et al. 2008). An elongated colon (called dolichocolon or redundant colon) was believed to be a common cause of STC (Brummer et al 1962; Davis 1960; Kantor 1931, 1934). Although, this concept has been recently challenged (Muller-Lissner et al 2005) it still persists in the literature (Gillick, Tazawa , 2001; Ripetti et al., 2006; Tomita, Howard, 2008). The recent lack of acceptance of elongation as a possible exacerbating factor in STC, may be due to difficulty in envisaging a mechanism by which colonic elongation might affect colon transit. The peristaltic reflex that causes the propulsion of fecal matter along the small and large intestine was discovered over 100yrs ago by Bayliss and Starling (1899, 1900) at Oxford University. Despite over a 100yrs of GI research, no additional intrinsic reflexes were discovered until we reported a powerful reflex in the large bowel that appears to underlie colonic storage and slow transit. This reflex, which is triggered by physiological levels of colonic elongation rather than radial distension, is highly likely to be clinically important since the dominant effect of elongation appears to be the activation of myenteric, mechanosensory descending interneurons that release nitric oxide to depress intrinsic neural circuits underlying peristalsis and secretion. Conversely, colonic shortening, as appears to occur in colitis, switches off this reflex leading to enhanced neuronal excitability and diarrhea. To determine how changes in this elongation reflex might be altered in disease states we are in the process of purchasing a dynamic fluorescent imaging set-up from American Companies with the ARRA stimulus money ($99,992) that was awarded to us. This includes a fast EMCCD camera and Upright microscope with water immersion lenses that will enable Eamonn Dickson (Postdoctoral Fellow) and Dante Heredia (Graduate Student) to assess the changes in activity in activity in many different enteric neurons, smooth muscle and pacemaker cells (ICC) within the colon following the induction of constipation and colitis. The use of this equipment will determine, for the first time, how these cells change their activity and connectedness in diseased states during constipation and colitis, so that we can design appropriate therapeutic/pharmacological interventions.
Project Description: We expect that during constipation there will be significant changes in the activity of enteric neurons, pacemaker cells and smooth muscle that underlie enteric elongation reflexes in the large bowel. This will lead to hypomotility and slowed transit in the large bowel. In the First Quarter we will purchase and set up the new equipment that will be purchased from American Companies and develop several animal models (guinea-pigs and mice) of constipation. In the Second, Third and Forth quarters we will assess how colonic motor patterns have been altered in these diseased models, and correlate the changes in enteric neurons, pacemaker cells and smooth muscle during constipation. These studies will lead, for the first time, to a new comprehensive investigation of the causes and changes underlying chronic constipation and therefore to increased employment of staff due to significant funding opportunities.
Jobs Summary: None to date. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 20, 2009. Help expand these official descriptions using the wiki below.