Short bowel syndrome (SBS) results from the surgical loss of a significant of small intestinal length. In response to this loss, an adaptation response occurs in the remaining bowel characterized by increased enterocyte proliferation leading to taller villi, deeper crypts, and an expanded mucosal surface area. The significance of adaptation is revealed in SBS patients who ultimately are able to wean completely from intravenous (IV) nutrition over time. If insufficient, the need for IV nutrition and its allied morbidity is permanet. Besides enhanced enterocyte proliferation, we have revealed that adaptation is associated with new blood vessel growth (angiogenesis) within the intestine. Further, we have found that SBR is associated with diminished oxygen delivery and elevated levels of hypoxia-inducible factor-alpha (HIF1a). Finally, resection-induced angiogenesis is associated with increased expression of the proangiogenic chemokine (C-X-C) ligand 5 (CXCL5). The significance and mechanism(s) for resection-associated angiogenesis are presently unknown. This project seeks to test the overarching hypothesis that angiogenesis is required for normal intestinal adaptation. The significance of angiogenesis in SBR-induced intestinal adaptation will be examined in the following aims:
Aim 1 will determine the mechanism for angiogenesis in response to SBR-induced intestinal hypoxia by first characterizing the effects of SBR and hypoxia on epithelial and endothelial HIF-1a and EGFR expression, and EGFR activity. Next, we will elucidate the effect of impaired epithelial or endothelial EGFR signaling on O2 delivery, HIF1a expression and intestinal angiogenesis after SBR. Finally, we will determine the effects of impaired epithelial or endothelial HIF1a expression on O2 delivery and intestinal angiogenesis after SBR.
In Aim 2, we will determine the mechanism for increased CXCL5 expression following SBR by determining the effect of disrupted intestinal endothelial or epithelial EGFR or HIF1a on CXCL5 expression in vitro and in vivo. We will also determine whether HIF1a is a direct transcription activator of CXCL5 expression.
In Aim 3, we will determine the contribution of CXCL5 expression and angiogenesis to functional adaptation by elucidating the metabolic consequences of perturbed angiogenesis. We will also define the effect of adenoviral-directed endothelial overexpression of HIF1a, EGFR, and CXCL5 on resection-associated angiogenesis and adaptation responses. Characterization of a precise mechanism for adaptation and how this process can be accelerated is therefore critical toward our long-term goal of developing more effective therapy for patients who have suffered massive intestinal loss.
After massive intestinal resection, the remnant bowel tries to compensate via a process termed adaptation. The overall goals of this project are to fully understand the process of adaptation and intestinal re-growth. This information is critical for the development of new therapeutic strategies to enhance this process, thereby saving lives of patients with short gut syndrome.
| Warner, Brad W (2016) The Pathogenesis of Resection-Associated Intestinal Adaptation. Cell Mol Gastroenterol Hepatol 2:429-438 |
| Diaz-Miron, Jose; Sun, Raphael; Choi, Pamela et al. (2015) The effect of impaired angiogenesis on intestinal function following massive small bowel resection. J Pediatr Surg 50:948-53 |
