Protein Kinase A and Intestinal Pseudo-obstruction

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DESCRIPTION (provided by applicant): Chronic intestinal pseudo-obstruction (CIP) is an intestinal motility disorder of heterogeneous etiology that has been defined as "a severe, disabling disorder characterized by repetitive episodes or continuous symptoms and signs of bowel obstruction, including radiographic documentation of dilated bowel with air-fluid levels, in the absence of a fixed, lumen-occluding lesion" (Rudolph et al, 1997). In pediatric CIP the pattern of small bowel distention can vary from patient to patient. In some cases the duodenum and proximal jejunum are specifically affected, while in other cases the ileum and proximal colon are selectively affected. Because of this variability in presentation it is exceedingly difficult to identify the etiology of, and treat CIP. Recent advances in our understanding of the CIP have come from the use of various animal models. Most prominent among these have been targeted genetic manipulations in mice. The research described in this proposal examines a novel murine model of CIP that results from inhibition of protein kinase A (PKA) in the developing neural crest and mature enteric nervous system. The experiments proposed in the first specific aim will utilize standard histological and immunohistochemical methods to quantify effects of PKA inhibition on neuronal and glial cell number and identify effects on specific subtypes of enteric neurons. The experiments proposed in the second specific aim will test the hypothesis that inhibition of the GDNF/Ret signal transduction pathway contributes to the molecular etiology of the observed pseudo-obstruction. This research will establish members of the PKA signal transduction pathway as new candidate genes to examine in cases of CIP without a known cause and could contribute to the discovery of novel therapeutic targets for non-surgical treatment of this disease.