The intestinal epithelium forms a dynamic barrier between the organism and various external factors present within the lumen, including commensal and pathogenic bacteria, dietary intake, gastrointestinal secretions and drugs. In inflammatory bowel disease (IBD), the epithelial barrier is repeatedly disrupted during flares of inflammation, allowing for increased exposure to infectious agents and toxins that exacerbate the existing inflammatory condition. Thus, rapid repair of epithelial breeches is critical for limiting mucosal inflammation and healing ulcerated lesions in these patients. Kruppel-like factor 5 (KLF5) is a member of a family of transcription factors that function in the regulation of diverse cellular processes, including development, proliferation and differentiation. KLF5 is highly expressed in epithelial cells in proliferating regions of the gut, and has been shown to be activated by a number of stress stimuli, including exposure to bacterial components and injury. In this proposal, we provide preliminary data that KLF5 is activated in epithelial cells at ulcer margins in the colon following injury with the chemical irritant, dextran sodium sulfate (DSS). Furthermore, mice with heterozygous expression of Klf5 (Klf5) exhibit increased sensitivity to DSS and show reduced expression of the wound healing marker, EGFR and reduced migration of epithelial cells to restore the epithelial barrier at ulcer margins. Based on these results, we hypothesize that KLF5 promotes the healing of damaged intestinal tissues through activation of gene targets that enhance restoration of the epithelial barrier. To test this hypothesis, two Specific Aims have been proposed: (I) to use an intestinal specific Klf5 conditional knockout as a definitive model for examining the role of KLF5 in epithelial restitution and wound healing and (II) to identify targets of KLF5 that are important for epithelial migration and wound repair using in vitro manipulation of KLF5 expression and wounding assays. By identifying factors necessary for epithelial restitution, we can provide potential therapeutic targets for enhancing wound healing in IBD patients.
One of the major complications of inflammatory bowel disease (IBD) is chronic disruption of the intestinal epithelium which exacerbates and prolongs the disease. Understanding how the mucosa is repaired and identifying key molecules involved in restitution of the epithelial barrier can provide potential therapeutic targets directed at mucosal healing for IBD patients.
| McConnell, Beth B; Kim, Samuel S; Yu, Ke et al. (2011) Krüppel-like factor 5 is important for maintenance of crypt architecture and barrier function in mouse intestine. Gastroenterology 141:1302-13, 1313.e1-6 |
| McConnell, Beth B; Kim, Samuel S; Bialkowska, Agnieszka B et al. (2011) Kruppel-like factor 5 protects against dextran sulfate sodium-induced colonic injury in mice by promoting epithelial repair. Gastroenterology 140:540-549.e2 |
| Ghaleb, Amr M; McConnell, Beth B; Kaestner, Klaus H et al. (2011) Altered intestinal epithelial homeostasis in mice with intestine-specific deletion of the Kruppel-like factor 4 gene. Dev Biol 349:310-20 |
| McConnell, Beth B; Yang, Vincent W (2010) Mammalian Kruppel-like factors in health and diseases. Physiol Rev 90:1337-81 |
| Du, James X; McConnell, Beth B; Yang, Vincent W (2010) A small ubiquitin-related modifier-interacting motif functions as the transcriptional activation domain of Kruppel-like factor 4. J Biol Chem 285:28298-308 |
