Interstitial Cystitis (IC) is a chronic irritative voiding syndrome that occurs without objective evidence of disease and is characterized by urinary frequency, nocturia, urgency, suprapubic pressure, and bladder or pelvic pain. The etiology(s) is currently unknown, and there are no reliably effective treatments. Many patients are left to suffer for the rest of their lives with this incapacitating condition. We hypothesize that IC develops when a barrier defect induces the expression of neuropeptides that transmit signals in the central nervous system (CNS), establishing the neuropathological hallmarks of the disease. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a leading candidate neuropeptide in the regulation of bladder function and upregulates in bladder afferent cells in the dorsal root ganglia (DRG) in cystitis models. It has been demonstrated recently that PACAP antagonists delivered intrathecally or intravesically can improve bladder overactivity in rodents with cystitis. Here we propose to develop two transgenic mouse models of PACAP over-expression in a tissue-specific manner to evaluate the role of this factor in the neurotrophic mechanisms and lower urinary tract plasticity associated with cystitis. These mouse models will have broad appeal to address not only PACAP's contribution to micturition reflexes, but also PACAP's role in nociceptive mechanisms in general. In a somatic mosaic model, PACAP38 will be over-expressed selectively in bladder sensory neurons following a direct bladder wall injection of a recombinant retrovirus that expresses the cDNA from the neuronal enolase specific promoter. We will also make mice that harbor a PACAP38 transgene whose transcription is controlled by a tetracycline-inducible promoter. These mice (TREPACAP38) will be crossed with our UPII-rtTA transgenic mice that express the reverse tetracycline transactivator only in urothelial cells. These bitransgenic mice (Uro-TetON-PACAP38) will receive doxycycline in their drinking water to evaluate the effect of drug-inducible PACAP over-expression in the bladder. Initial studies to validate the in vivo expression of PACAP38 and its effects on voiding function will be performed. If successful, the mice will be distributed to interested labs to assist with the rigorous characterization of the models as they relate to the neurochemical organization of voiding function.
| Rashid, Hani H; Reeder, Jay E; O'Connell, Mary J et al. (2004) Interstitial cystitis antiproliferative factor (APF) as a cell-cycle modulator. BMC Urol 4:3 |
