Interstitial cystitis (1C) is a chronic painful bladder disorder with which approximately 1 million Americans are afflicted. The etiology of 1C is unknown, and there is currently no reliably effective treatment. It is therefore important to continue to search for a cause of this debilitating disorder, in order to systematically devise an effective therapy. We have discovered, purified, characterized, and synthesized a toxic glycopeptide (antiproliferative factor, or APF) that appears to be made uniquely by bladder epithelial cells from 1C patients. APF is a small sialoglycopeptide whose peptide backbone bears 100% homology to a segment from the 6th transmembrane portion of Frizzled 8, a receptor that functions in Wnt signalling. APF has been shown to cause specific changes in normal bladder epithelial cells that mimic changes seen in 1C cells in vitro, including profoundly inhibited cell proliferation, specifically altered gene expression, decreased tight junction formation with increased epithelial monolayer permeability, and decreased production of heparin-binding epidermal growth factor-like growth factor (HB-EGF), Because bladder epithelial thinning or ulceration, altered gene expression, leakiness, and decreased urine HB-EGF levels have also been described in 1C patients in vivo, APF may play a direct role in the pathogenesis of 1C. Additional studies on the structure and mechanism of activity for this toxin may therefore be helpful for the development of specific therapies designed to inhibit its activity. Therefore, we propose to learn more about the structure/function relationship of this frizzled-related glycopeptide and the role of specific Wnt signaling pathways in mediating its effects. In addition, we will look for evidence that APF interacts with a specific cell membrane receptor, and determine the relative ability of recombinant human HB-EGF, inactive synthetic APF congeners, and antibodies raised against active synthetic APF congeners to inhibit the effects of APF on bladder epithelial cells. Data from these studies should yield valuable information regarding the structure and mechanism of activity for APF, and may also lead to the identification of potential therapies for this disorder. ? ? ?
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