PDE5 Inhibition of Afferents and Interstitial Cells in Overactive Mouse bladders - YR 1

Project Details


This proposal comprises a two center international collaboration to draw upon complementary expertise in answering key issues of pathophysiological mechanisms and therapeutic potentials in overactive bladder (OAB) and neurogenic bladder dysfunction (NBD). The collaboration will study the influence of phosphodiesterase type 5 (PDE5) inhibitors on sensory and motor behavior of the lower urinary tract (LUT) using established models of T8-T9 spinal cord transection (SCT) for NBD and intravesically instilled transient receptor potential ankyrin 1 (TRPA1) receptor agonist, acrolein, for OAB. The University of Pittsburgh group has developed new in vitro approaches for studying peripheral LUT function using isolated tissues and cells, while the University of Bristol team has developed new in situ approaches for studying CNS sensory and motor function and the reflexes controlling the LUT. The two research teams have a good record of collaboration, evidenced by successfully obtaining preliminary data in this technically challenging scientific area, funded in part, by a pilot grant from the International Continence Society to the Co-PI's. Further collaboration between these centers will increase our knowledge of integrative (patho) physiology of the LUT and the potential therapeutic role of PDE5 inhibitors. There are three specific aims: Specific Aim1: To measure effects of PDE5 inhibition on Aδ- versus C-fiber afferent firing and neuropeptide release, in whole bladder sheets and cross sections from normal, SCT and acrolein instilled mice. Specific Aim2: To measure effects of PDE5 inhibition on storage and voiding reflexes in normal and acrolein instilled decerebrate arterially perfused mice (DAPM) before and after acute brainstem/SCT. Specific Aim3: To measure effects of PDE5 inhibition on in-line dissociated urothelial, interstitial and smooth muscle cells and bladder wall cross sections from control versus SCT mice.
Effective start/end date1/10/1430/09/15