Signaling Pathways Associated with Crypt Fission

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Following massive intestinal loss, an adaptive process in the remaining bowel results in the expansion of mucosal surface area to enhance digestion and absorption of nutrients. Intestinal failure occurs in patients who are unable to sufficiently compensate, resulting in the prolonged requirement of parenteral nutrition to sustain adequate nourishment and fluid balance. My ongoing K08 work using a murine model of small bowel resection to investigate the role of secretory lineages in the ileum during adaptation, together with recent reports from other investigators, has highlighted the fact that there are marked regional differences in the adaptive response. These findings led to the development of a murine model of ileocecal resection (ICR) to allow evaluation of adaptation in the jejunum. This model demonstrates that part of the long-term adaptive response in the jejunum occurs due to an expansion of intestinal stem cells increasing the total number of crypts by crypt fission. This mechanism increases the caliber of the intestine without changes in proliferation, crypt depth or villus height when compared to sham-operated animals. To my knowledge this is the first report of crypt fission being a component of the adaptive response. An increase in crypt number by crypt fission has previously been associated with intestinal stem cell expansion during postnatal development, and as a result of intestinal stem cell loss due to radiation or chemotherapy exposure. Although the mechanisms driving crypt fission in these various conditions have not been evaluated, recent studies in transgenic mice have demonstrated inhibition of bone morphogenic protein (BMP) signaling results in the activation of Wnt/(-catenin pathways increasing crypt fission. The goal of this R03 application is to address the hypothesis that inhibition of BMP signaling results in the activation of the Wnt/(-catenin pathways associated with crypt fission during development and following ICR. To achieve this, we will assess changes in the expression of candidate pathway genes using quantitative in situ hybridization and immunohistochemistry comparing animals during development [P7 (low fission) vs. P21 (high fission)] and 7 d following surgical resection [sham-operation (low fission) vs. ICR (high fission)]. Differentially expressed transcripts between these groups identified by gene expression microarrays will be compared to identify common changes associated with crypt fission. These studies will provide important insight into the long-term adaptive mechanisms that occur following intestinal loss, leading to potential therapies for patients suffering from intestinal failure.