After massive small bowel resection (SBR), the remaining intestine compensates by a critical process termed adaptation. Adaptation is largely a mitogenic signal for increased enterocyte proliferation, thus generating taller villi, and greater bowel caliber and length. While the mechanism for resection-induced enterocyte proliferation is presently unknown, we have established that epidermal growth factor receptor (EGFR) signaling is critical. Using p21waf1/cip1-null mice, we determined that proliferation was paradoxically abolished after SBR in the absence of this cyclin dependent kinase inhibitor. As an extension of these observations, we propose the global hypothesis that EGFR signaling regulates the expression of p21 to initiate enterocyte proliferation after SBR. To test this hypothesis, our aims are: 1) Delineate the effects of SBR and EGFR manipulations on intestinal p21 expression. Laser capture microdissection (LCM) microscopy wilt be employed to establish a temporal, regional, and enterocyte-specific expression of p21 mRNA and protein along the crypt-villus axis after SBR. Both in vivo and in vitro models of adaptation will be studied under conditions of EGFR stimulation and inhibition. 2) Determine the mechanism for EGFR regulation of p21. To test the hypothesis that EGFR governs p21 expression via STAT, we will elucidate STAT expression and activation after SBR in vivo and in vitro. We will then delineate p21 expression during adaptation in vitro after inhibition of STAT and in vivo in STATl-null mice. 3) Determine the mechanism for blocked postresection proliferation in p21-null mice.
This aim will test the hypothesis that postresection proliferation is prevented in p21-null mice because of compensatory increased expression of p27kip1. A temporal and cell compartment profile of P27 expression will be determined in p21-null mice. The magnitude of adaptation will then be elucidated in p27-null and p21/p27 double-null mice. These studies will contribute substantially toward an enhanced understanding of critical early signaling pathways involved in the regulation of adaptation. This information is fundamental toward the future development of safe and effective clinical therapy designed to amplify this important process.
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