The intestinal epithelium is among the most rapidly proliferating tissues in the body, renewing itself once every 3 to 5 days. The balance between cell proliferation and cell death is believed to be the critical event orchestrating these dynamic changes in the intestine. The steady-state of epithelial cells is maintained by a process in which stem cells proliferate at the base of the crypt. Daughter cells differentiate into specialized cells which migrate up the crypt along the basement membrane to replace cells that are continuously shed at the luminal surface. The exfoliating epithelial cell undergoes a process known as programmed cell death (PCD) or apoptosis. Yet the mechanisms which maintain this homeostasis and control apoptosis are largely unknown. We propose that regulation of the death machinery is an essential component of intestinal epithelial homeostasis and that altered signaling of apoptosis may contribute to colonic neoplasia. The observation that only cells at the very tip of the crypt or villus undergo apoptosis suggests that detachment from the basement membrane and/or disruption of cell-cell contacts may trigger cell death. The focus of this proposal is define the mechanism of detachment-induced cell death. We will use our extensive expertise in the cell biology of intestinal epithelial cells and state-of-the-art techniques available in our laboratory to study the triggering, initiation, amplification, and execution of the cell death machinery to test the following central hypothesis: Homeostasis in the intestinal epithelium is maintained by linking cell growth and cell death to anchorage dependence. Loss of integrin occupancy leads to inhibition of cell proliferation and induction of programmed cell death. A corollary of this thesis predicts that colonic carcinomas result from aberrant cell signaling which mimics integrin occupancy, giving neoplastic cells the capability of unregulated growth. At the same time, the normal regulatory balance provided by the process of apoptosis, which should limit the rate of tissue accumulation, is lost. This breakdown in regulation results in disruption of homeostasis in the epithelium, which may contribute to an increased risk for colorectal cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Ault, Grace S
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Stallion, Anthony; Kou, Tzuyung D; Latifi, Samir Q et al. (2005) Ischemia/reperfusion: a clinically relevant model of intestinal injury yielding systemic inflammation. J Pediatr Surg 40:470-7
Latifi, Samir Q; O'Riordan, Mary Ann; Levine, Alan D (2002) Interleukin-10 controls the onset of irreversible septic shock. Infect Immun 70:4441-6
Stallion, Anthony; Kou, Tzuyung D; Miller, Kelly A et al. (2002) IL-10 is not protective in intestinal ischemia reperfusion injury. J Surg Res 105:145-52
Grossmann, J; Artinger, M; Grasso, A W et al. (2001) Hierarchical cleavage of focal adhesion kinase by caspases alters signal transduction during apoptosis of intestinal epithelial cells. Gastroenterology 120:79-88
Itoh, J; de La Motte, C; Strong, S A et al. (2001) Decreased Bax expression by mucosal T cells favours resistance to apoptosis in Crohn's disease. Gut 49:35-41
Levine, A D (2000) Apoptosis: implications for inflammatory bowel disease. Inflamm Bowel Dis 6:191-205