Short bowel syndrome resulting from diminished intestinal absorptive function is a major cause of morbidity and impaired quality of life. Although transplantation is an alternative for a small subset of selected patients, strategies designed to increase the function of the remnant intestine are clearly still needed. Following loss of small bowel surface area, the gut undergoes an adaptive response characterized by crypt cell hyperplasia, villus lengthening, and increased absorptive function. The ultimate goal of this project is to elucidate the mechanisms underlying the adaptive response to facilitate the design of rational nutritional and pharmacological regimens to maximize gut adaptation, hi the current grant period, we have used rodent resection models to confirm the importance of vitamin A as a putative regulator of the adaptive response. The most compelling supportive evidence includes observations that vitamin A deficiency impaired adaptation and vitamin A administration augmented adaptation. The following hypotheses will be addressed in the current proposal: l.Retinoids directly modulate the intestinal adaptive response to loss of functional bowel area, via effects on cell death as well as crypt cell proliferation, epithelial cell adhesion and migration. 2. Retinoid X Receptor (RXR) interactions (heterodimerization) with retinoic acid receptors (RAR), peroxisome proliferator activated receptors (PPAR), and/or other nuclear receptors are an important mechanism for retinoid modulation of adaptation. 3. Retinoids inhibit apoptosis in the adapting gut via effects on the Bcl2/Bax family of apoptotic regulators.
The specific aims are: 1. Define the mechanisms by which vitamin A modulates intestinal adaptation by investigating the effects of vitamin A administration in rodent resection models. 1 A. Define the effects of varying the timing and dosing of exogenous retinoids on the initiation, maintenance and enhancement of the adaptive response. IB Define the role of CRBP II and vitamin A metabolism in intestinal adaptation. 2. Define the mechanisms of vitamin A actions in adaptation by studying the role of RARs and RXR heterodimerization with RARs, PPARs and farnesoid X receptors. 3. Define the mechanisms of vitamin A actions in adaptation by studying how retinoids affect apoptotic pathways in the gut.
