This is the first revision of a competitive renewal R01 application. Following the loss of small bowel surface area, the intestine undergoes an adaptive response characterized by crypt cell hyperplasia, villus lengthening and increased absorptive function. Little is known of the underlying molecular and cellular mechanisms of this adaptation. The ultimate goal of this project is to elucidate these mechanisms to facilitate the design of nutritional and pharmacological regimens to maximize intestinal adaptation. The investigator has previously used a rat intestinal resection model to clone a group of genes that are regulated in the adapting remnant intestine. These studies have implicated vitamin A as a potential regulator of the adaptive response. Additional evidence supporting a role for vitamin A in adaptation has come from the current support period demonstrating that: (1) retinoic acid stimulates crypt cell proliferation in the early postoperative phase of adaptation; (2) the induction of vitamin A deficiency completely blocks the adaptive response; and (3) vitamin A deficiency may impair adaptation by stimulating apoptosis. Preliminary studies have implicated modulation of programmed cell death as an important contributor to the adaptive response. The following hypotheses will be addressed in this revised proposal: (1) alterations in the rate of programmed cell death contribute to the intestinal adaptive response. These alterations are mediated by the BcL2/Bax family of apoptosis regulators; (2) 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.
The specific aims of this proposal are: (1) To define the role of apoptosis and identify proximal regulators of apoptosis in gut adaptation, using Bcl-2 and Bax knockout mice and transgenic mice that overexpress Bcl-2 in the small intestine. (2a) Define the role of retinoids in initiating and maintaining the adaptive response by investigating the effects of vitamin A administration on cell proliferation and apoptosis. (2b) Define the mechanisms by which vitamin A deficiency impairs adaptation following small bowel resection by analyzing alterations in apoptosis, cell adhesion and the extracellular matrix. The investigator will also determine whether early changes in CRBP II expression reflect a regulatory role in adaptation by examining the adaptive response in CRBP II knockout mice.
