UNIVERSITY OF CHICAGO, THE
Intestinal homeostasis is the essential and dynamic equilibrium of factors that maintain normalmucosal function, integrity, self-renewal, and host defense. In acute diseases, the pathogenic insult is self-limited and intestinal homeostasis is restored. In inflammatory bowel diseases (IBD), intestinalhomeostasis cannot be restored because of the persistence of chronic, destructive mucosal inflammation.However, less well considered is the possibility that countering mechanisms necessary for restoringintestinal homeostasis are impaired during and even after resolution of the offending insult. This proposalwill therefore examine the hypothesis that the inducible heat shock protein, Hsp70, is essential formaintaining intestinal homeostasis and that its deficient expression during inflammation contributes to thedevelopment of chronic colitis and colitis-associated colon cancer. Support for this notion comes from thefollowing observations: (1) Hsp70 has both potent cytoprotective and anti-inflammatory properties, (2)down-regulated expression of Hsp70 is observed in experimental and human colitis, rendering the mucosamore susceptible to injury and intensifying the inflammatory response, (3) gene-targeted deletion of Hsp70transforms the otherwise, self-limited, DSS-induced colitis to a chronic, ¿IBD¿-like colitis, and (4) afterAOM/DSS challenge, multi-focal, flat dysplasia-to-cancer sequence colon cancer develops in Hsp70-deficient mice as opposed to their wild-type counterparts that develop sporadic polyp-to-cancer sequencecolon cancer, and 5) robust Hsp70 expression is associated with sporadic human colon cancer, but notIBD cancer. Three specific aims are proposed to investigate the role of Hsp70 (in epithelial versus immune-derivedcells) in intestinal homeostasis and whether impaired expression caused by inflammation contributes tothe development of chronic colitis and IBD-like colon cancer. First, we will determine if Hsp70 is essentialfor maintenance of intestinal homeostasis and whether it down-regulated expression in acute inflammatoryand in immune-based models of colitis leads to chronic or more severe IBD-like colitis. Second, themechanism(s) causing the observed selective translational down-regulation of Hsp70 associated withintestinal inflammation and pro-inflammatory cytokines will be defined. Finally, we will investigate whetherthe loss of Hsp70 expression/function is necessary and sufficient for development of spontaneous andcarcinogen-induced colon cancer in mice with chronic colitis. A combination of in vitro and in vivoapproaches will be employed, the latter including novel models of gene-targeted-Hsp70 deletion andepithelial- or myeloid cell-specific Hsp70 transgene expression. The insights gained through these studieswill provide proof of principle that processes that impair intestinal homeostasis can contribute to thedevelopment of IBD and inflammation-associated colon cancer. Strategies to restore intestinalhomeostasis would therefore be important for preventing, treating, and changing the natural history ofinflammatory bowel diseases. This proposal will examine the hypothesis that the inducible heat shock protein,Hsp70, is essential for maintaining intestinal homeostasis and that its deficientexpression in inflamed mucosa contributes to the development of chronic colitis andcolitis-associated colon cancer. Strategies to restore Hsp70 expression in inflamedmucosa would be important for preventing, treating, and changing the natural history ofinflammatory bowel diseases.