This revised renewal application proposes studies aimed at defining the regulation and mechanisms of action of two intestinal epithelial heat shock proteins (hsp), hsp25/27 and hsp72, both exhibiting epithelial- and colon-specific expression in the gut. Both hsps have essential roles protecting the gut epithelium against many forms of stress, particularly those associated with inflammation such as oxidants. From new studies of IBD and of acute and chronic experimental colitis, the expression of both hsps is significantly impaired in areas of active inflammation, a finding that would likely render the mucosa highly susceptible to extensive and severe injury.
Three specific aims are proposed: (1) to further characterize the relative deficiency of hsp25/27 and hsp72 expression in areas of active mucosal inflammation, determine if perturbed expression alters the course of DSS-induced colitis, and identify potential mechanisms for selective hsp downregulation, (2) to define the determinants of normal colon- and epithelial-specific expression of hsp25 and hsp72, with particular attention to the role of colonic flora and mucosal immune cells, and (3) to understand how hsps protect four vital cell functions of intestinal epithelial cells (IEC). For the first specific aim, hsp27 and hsp72 expression and localization in normal and inflamed colons will be assessed. Unique mouse models expressing high or negligible colonic hsps will be studied to determine if the course of DSS induced colitis is mitigated by hsp presence. Potential """"""""hsp-suppressive"""""""" cytokines will be identified. Next, we will determine what aspects of enteric flora and mucosal immunocytes maintain the in vivo expression of hsp25 and hsp72. Specific luminal and lamina propria signals that maintain hsp expression will be determined by a combination of in vitro and in vivo approaches. Finally, we will determine how oxidants, major mediators of inflammation-associated stress and injury, impair specific and vital IEC functions, e.g. (1) Na absorption mediated by the Na-H exchanger, NHE3, (2) Na, K-ATPase function and basolateral-restricted expression, (3) mitochondrial and microtubular interaction and function, and (4) tight junction-mediated barrier function. How hsps limit the extent of oxidant-induced impairment of these functions will also be examined. A better understanding of natural defense mechanisms of the gut can be exploited to develop novel therapies aimed at restoring or augmenting the impaired hsp response in areas of active inflammation to limit the extent and severity of mucosal injury in IBD. ? ?
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