The aetiology of interstitial cystitis (IC) and other chronic inflammatory uropathies is not understood. We propose to develop a model system in which the urothelium will be studied in isolation from modulatory histio-environmental factors in order to address whether there is an inherent dysfunction in the urothelium, in at least a subset of painful bladder diseases. Our experimental strategy will be to remove modulatory histio-environmental factors by establishing urothelial cells from IC and control patients in a defined in vitro cell culture system. The model system will permit direct comparison of the phenotypic, functional and immunological characteristics of urothelial cells from IC and normal urothelium. We propose to use this system to test a novel hypothesis, namely that the disease is perpetuated by a failure of the urothelium to provide adequate barrier function against the ingress of urine, leading to tissue damage and consequent inflammation. We will further determine if this can arise due to an inherent defect of the urothelium itself, or due to abnormal responses to inflammatory cytokines produced as a consequence of transient infection or trauma. To these ends, we will study the urothelial cell cultures for their ability to a) Undergo differentiation, b) Form a functional barrier urothelium and c) Show a normal response to archetypal pro- and anti-inflammatory cytokines. The work will be important in establishing whether urothelial cells from patients with IC are inherently abnormal, or whether the aetiopathology of IC is secondary to other factors. The power of this approach lies in its capability of providing evidence of disease subsets and its potential to reveal targets for therapy.
| Smith, Nicholas J; Hinley, Jennifer; Varley, Claire L et al. (2015) The human urothelial tight junction: claudin 3 and the ZO-1?(+) switch. Bladder (San Franc) 2:e9 |
| Southgate, Jennifer; Varley, Claire L; Garthwaite, Mary A E et al. (2007) Differentiation potential of urothelium from patients with benign bladder dysfunction. BJU Int 99:1506-16 |
| Varley, Claire L; Garthwaite, Mary A E; Cross, William et al. (2006) PPARgamma-regulated tight junction development during human urothelial cytodifferentiation. J Cell Physiol 208:407-17 |
