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. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Mullins, Christopher V
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University of Maryland Baltimore
Internal Medicine/Medicine
Schools of Medicine
United States
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Yang, Wei; Kim, Yongsoo; Kim, Taek-Kyun et al. (2012) Integration analysis of quantitative proteomics and transcriptomics data identifies potential targets of frizzled-8 protein-related antiproliferative factor in vivo. BJU Int 110:E1138-46
Kim, Jayoung; Keay, Susan K; You, Sungyong et al. (2012) A synthetic form of frizzled 8-associated antiproliferative factor enhances p53 stability through USP2a and MDM2. PLoS One 7:e50392
Kim, Jayoung; Ji, Mihee; DiDonato, Joseph A et al. (2011) An hTERT-immortalized human urothelial cell line that responds to anti-proliferative factor. In Vitro Cell Dev Biol Anim 47:2-9
Yang, Wei; Chung, Yeun Goo; Kim, Yongsoo et al. (2011) Quantitative proteomics identifies a beta-catenin network as an element of the signaling response to Frizzled-8 protein-related antiproliferative factor. Mol Cell Proteomics 10:M110.007492
Keay, Susan; Kaczmarek, Piotr; Zhang, Chen-Ou et al. (2011) Normalization of proliferation and tight junction formation in bladder epithelial cells from patients with interstitial cystitis/painful bladder syndrome by d-proline and d-pipecolic acid derivatives of antiproliferative factor. Chem Biol Drug Des 77:421-30
Kim, Jayoung; Keay, Susan K; Freeman, Michael R (2009) Heparin-binding epidermal growth factor-like growth factor functionally antagonizes interstitial cystitis antiproliferative factor via mitogen-activated protein kinase pathway activation. BJU Int 103:541-6
Sun, Yan; Keay, Susan; Lehrfeld, Todd J et al. (2009) Changes in adenosine triphosphate-stimulated ATP release suggest association between cytokine and purinergic signaling in bladder urothelial cells. Urology 74:1163-8
Planey, Sonia L; Keay, Susan K; Zhang, Chen-Ou et al. (2009) Palmitoylation of cytoskeleton associated protein 4 by DHHC2 regulates antiproliferative factor-mediated signaling. Mol Biol Cell 20:1454-63
Kaczmarek, Piotr; Keay, Susan K; Tocci, Gillian M et al. (2008) Structure-activity relationship studies for the peptide portion of the bladder epithelial cell antiproliferative factor from interstitial cystitis patients. J Med Chem 51:5974-83
Kim, Jayoung; Keay, Susan K; Dimitrakov, Jordan D et al. (2007) p53 mediates interstitial cystitis antiproliferative factor (APF)-induced growth inhibition of human urothelial cells. FEBS Lett 581:3795-9

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