Information transfer from the cellular membrane to the nucleus involves several wall-characterized molecular signaling pathways that lead to transcriptional activation. One of the most important pathways of information transfer is the NF-kappaB (nuclear factor-kappaB) signaling pathway involved in the regulation of an exceptionally large number of genes responsible for a cellular response in an organ system such as the bladder to inflammation, infection, and other stressful cellular situations that requires rapid reprogramming of gene expression. While the exact etiology of Interstitial Cystitis (IC), a debilitating, chronic inflammatory syndrome of the bladder remains elusive, the common translational finding between proposed clinical etiologies is that they are all known to be cellular activators of the intracellular NF-kappaB signaling pathway. We hypothesize that the pathogenesis of the bladder response in IC is due to activation of the NF-kappaB signaling pathway. We will test this hypothesis by characterizing the NF-kappaB signaling pathway and regulated cellular genetic expression in bladder tissue (Specific Aim 1) as well as urothelial cell cultures (Specific Aim 2) from IC patients compared to controls. In addition to establishing NF-kappaB signaling as the essential pathway for the bladder response in IC, the specific aims will determine whether the activated signaling represents a dysfunctional (aberrant internal cellular control of the signaling pathway) versus functional (signaling pathway response to external cellular stimulation) urothelial response to extra-cellular stimulation. The significance of determining whether the activation of the NF-kappaB signaling response is functional verses dysfunctional is related to the development of novel clinical markers as wall as therapeutic interventions directed at the pathogenesis of IC. Our IC bladder tissue in Specific Aim 1 will be used to corroborate potential diagnostic gene (dysfunctional inhibitor or kinase proteins due to gene mutations) or post-transcription clinical markers that give rise to aberrant NF-kappaB regulation in urothelial cell culture experiments from Specific Aim 2. Future aims for developing treatments based on the pathogenesis of IC from activated NF-kappaB signaling will focus on modulation of the extra-cellular stimulation and downregulation of acute and chronic hyper-activation in the functional response versus development of interventions that address the molecular signaling defects associated with the dysfunctional response.
