Our laboratory discovered an anti-proliferative factor (APF) that is a sialoglycopeptide inhibitor of bladder epithelial cell proliferation secreted specifically by bladder epithelial cells from patients with interstitial cystitis (IC), a disorder commonly associated with denudation or thinning of the bladder epithelium. APF was discovered to be the active factor in urine from IC patients that reversibly inhibited the growth of bladder epithelial cells in vitro. The specificity of APF for urine from IC patients (vs. normal controls or patients with a variety of other urogenital disorders) indicates that it may be useful as a diagnostic marker for IC and that it may play an important role in the pathogenesis of this disorder. APF is the first naturally occurring, low molecular weight negative growth regulator to have been identified and completely characterized. The peptide sequence of APF is identical to residues 541–549 of the 6th transmembrane domain of frizzled 8, a Wnt ligand receptor. The glycosyl moiety of APF consists of sialic acid a-2,3 linked to galactose b1–3-N-acetylgalactosamine, which is a-O-linked to the N-terminal threonine of the peptide.
APF has been shown to profoundly inhibit the proliferation of both normal bladder epithelial cells and bladder carcinoma cells in vitro. Furthermore, APF can induce multiple changes in the pattern of normal bladder epithelial cell gene expression including decreased production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and increased production of E-cadherin, resulting in a more differentiated bladder epithelial cell phenotype, similar to changes seen in cells explanted from IC patient biopsies. APF was also recently determined to decrease tight junction protein (zonula occludens-1 and occludin) production and increase paracellular permeability of normal bladder epithelial cell monolayers similar to abnormalities seen in cells from IC patients in vitro, providing additional evidence that it may play a pivotal role in the pathogenesis of IC.
We recently identified a functional receptor for APF on bladder epithelial cells (CKAP4) and are now determining the role of this receptor in mediating APF activity in both normal bladder epithelial cells and uroepithelial carcinomas. Our lab is also attempting to identify substances that inhibit APF production or activity as potential therapies for IC. In collaboration with investigators at the NCI, we are testing various synthetic APF congeners to learn more about structural requirements for activity, with the goal of developing low molecular weight inhibitors of APF activity and urologic carcinoma proliferation.
I am also the local Principal Investigator for the multicenter Shingles Prevention Study (VA Cooperative Study #403), a trial of varicella zoster vaccine for the prevention of shingles and associated complications in persons 60 years of age and older. The currently available shingles vaccine became licensed as a result of findings during the first 6 years of this trial. The Baltimore VA site is now performing long-term follow-up of vaccinees to determine the durability of protection.
Keay S, Zhang C-O, Hise M, Trifillis AL, Hebel JR, Jacobs SC, and Warren JW. Decreased 3H-Thymidine Incorporation by Human Bladder Epithelial Cells Following Exposure to Urine from Interstitial Cystitis Patients. J. Urol. 1996; 156:2073-2078.
Keay S, Kleinberg M, Zhang C-O, Hise MK, Warren JW. Bladder Epithelial Cells from Interstitial Cystitis Patients Produce an Inhibitor of HB-EGF Production. J. Urol. 2000; 164: 2112-2118.
Keay S, Zhang C-O, Shoenfelt J, Erickson DR, Whitmore K, Warren JW, Marvel R, Chai T. Sensitivity and Specificity of Antiproliferative Factor, Heparin-Binding Epidermal Growth Factor-Like Growth Factor, and Epidermal Growth Factor as Urine Markers for Interstitial Cystitis. Urology 2001; 57 (6 Suppl 1): 9-14.
Zhang C-O, Li Z-L, Shoenfelt JL, Kong C-Z, Chai TC, Erickson DE, Peters KM, Rovner ES, Keay S. Comparison of APF Activity and Epithelial Growth Factor Levels in Urine from Chinese, African American and Caucasian American IC Patients. Urology 2003; 61: 897-901.
Keay S, Zhang C-O, Shoenfelt JL, Chai TC. Decreased In Vitro Proliferation of Bladder Epithelial Cells from Patients with Interstitial Cystitis. Urology 2003; 61: 1278-1284.
Keay S, Seillier-Moiseiwitsch F, Zhang C-O, Chai TC, Zhang J. Changes in Human Bladder Cell Gene Expression Associated with Interstitial Cystitis or Antiproliferative Factor Treatment. Physiological Genomics 2003; 14: 107-115.
Keay S, Takeda M, Tamaki M, Hanno P. Current and Future Directions in Diagnostic Markers in IC. Intl. J. Urol. 2003; 10 (Suppl): S27-S30.
Keay S, Zhang C-O, Chai T, Warren J, Koch K, Grkovic D, Colville H, Alexander R. Antiproliferative Factor, Heparin-Binding Epidermal Growth Factor-Like Growth Factor, and Epidermal Growth Factor in Men with Interstitial Cystitis vs. Chronic Pelvic Pain Syndrome. Urology 2004; 63:22-6.
Van QN, Klose JR, Lucas DA, Prieto D, Luke B, Collins J, Burt SK, Chmurny GN, Issaq HJ, Conrads TP, Veenstra TD, Keay SK. The Use of Urine Proteomic and Metabonomic Patterns for the Diagnosis of Interstitial Cystitis and Bacterial Cystitis. Disease Markers 2004; 19: 169-183.
Rashid HH, Reeder JE, O'Connell MJ, Zhang C-O, Messing EM, Keay SK. Interstitial Cystitis Anti-proliferative Factor (APF) as a Cell-Cycle Modulator. BMC Urology 2004; 4:3.
Keay SK, Szekely Z, Conrads TP, Veenstra TD, Barchi JJ, Jr., Zhang C-O, Koch KR, Michejda CJ. An Antiproliferative Factor from Interstitial Cystitis Patients is a Frizzled 8 Protein-Related Sialoglycopeptide. Proc. Natl. Acad. Sci,, USA 2004; 101:11803-11808.
Keay S., Chai T. New Theories in Interstitial Cystitis. Nature Clinical Practice Urology 2004; 1: 85-89.
Erickson DR, Tomaszewski JE, Kunselman AR, Bentley CM, Peters KM, Rovner ES, Demers LM, Wheeler MA, Keay SK. Do the NIDDK Cystoscopic Criteria Associate with Other Clinical and Objective Features of Interstitial Cystitis? J. Urol. 2005; 173: 93-97.
Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW, Jr., Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh SS, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kiriakides TC, Chan CY, Chan ISF, Wang WWB, Annunziato PW, Silber JL. Varicella-Zoster Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia. New Eng J Med 2005; 352: 2271-2284.
Hanno P, Keay S, Moldwin R, Van Ophoven A. International Consultation on IC - Rome, September 2004/Forging an International Consensus: Progress in Painful Bladder Syndrome/Interstitial Cystitis. Int Urogynecol J Pelvic Floor Dysfunct. 2005; 16 Suppl 1:S2-S34.
Zhang C, Wang J, Koch K, Keay S. Regulation of Tight Junction Proteins and Bladder Epithelial Paracellular Permeability by an Antiproliferative Factor from Interstitial Cystitis Patients. J. Urol. 2005; 174: 2382-7.
Conrads TP, Tocci GM, Hood BL, Zhang C-O, Guo L, Koch KR, Michejda CJ, Veenstra TD, Keay SK. CKAP4/p63 is a Receptor for the Frizzled-8 Protein-Related Antiproliferative Factor from Interstitial Cystitis Patients. J Biol Chem. 2006; 281(49): 37836-43.
Erickson DR, Kunselman AR, Bentley CM, Peters KM, Rovner ES, Wheeler MA, Demers LM, Keay SK. Changes in Urine Markers and Symptom Scores after Bladder Distention for Interstitial Cystitis. J Urol. 2007; 177(2): 556-60.
Coowanitwong I, Keay SK, Natarajan K, Garimella TS, Mason CW, Bauer KS. Toxicokinetic Study of Recombinant Human Heparin-Binding Epidermal Growth Factor-Like Growth Factor (rhHB-EGF) in Female Sprague Dawley Rats. In Press, Pharmaceutical Research, 2007.
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