Intestinal homeostasis is the essential and dynamic equilibrium of factors that maintain normal mucosal 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), intestinal homeostasis cannot be restored because of the persistence of chronic, destructive mucosal inflammation. However, less well considered is the possibility that countering mechanisms necessary for restoring intestinal homeostasis are impaired during and even after resolution of the offending insult. This proposal will therefore examine the hypothesis that the inducible heat shock protein, Hsp70, is essential for maintaining intestinal homeostasis and that its deficient expression during inflammation contributes to the development of chronic colitis and colitis-associated colon cancer. Support for this notion comes from the following 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 mucosa more susceptible to injury and intensifying the inflammatory response, (3) gene-targeted deletion of Hsp70 transforms the otherwise, self-limited, DSS-induced colitis to a chronic, IBD-like colitis, and (4) after AOM/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 sequence colon cancer, and 5) robust Hsp70 expression is associated with sporadic human colon cancer, but not IBD cancer.
Three specific aims are proposed to investigate the role of Hsp70 (in epithelial versus immune-derived cells) in intestinal homeostasis and whether impaired expression caused by inflammation contributes to the development of chronic colitis and IBD-like colon cancer. First, we will determine if Hsp70 is essential for maintenance of intestinal homeostasis and whether it down-regulated expression in acute inflammatory and in immune-based models of colitis leads to chronic or more severe IBD-like colitis. Second, the mechanism(s) causing the observed selective translational down-regulation of Hsp70 associated with intestinal inflammation and pro-inflammatory cytokines will be defined. Finally, we will investigate whether the loss of Hsp70 expression/function is necessary and sufficient for development of spontaneous and carcinogen-induced colon cancer in mice with chronic colitis. A combination of in vitro and in vivo approaches will be employed, the latter including novel models of gene-targeted-Hsp70 deletion and epithelial- or myeloid cell-specific Hsp70 transgene expression. The insights gained through these studies will provide proof of principle that processes that impair intestinal homeostasis can contribute to the development of IBD and inflammation-associated colon cancer. Strategies to restore intestinal homeostasis would therefore be important for preventing, treating, and changing the natural history of inflammatory bowel diseases. This proposal will examine the hypothesis that the inducible heat shock protein, Hsp70, is essential for maintaining intestinal homeostasis and that its deficient expression in inflamed mucosa contributes to the development of chronic colitis and colitis-associated colon cancer. Strategies to restore Hsp70 expression in inflamed mucosa would be important for preventing, treating, and changing the natural history of inflammatory bowel diseases.
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