Effects of Inflammation in a Mouse Model of Interstital Cystitis

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DESCRIPTION (provided by applicant): Interstitial cystitis (IC) is an inflammatory chronic bladder disorder characterized by suprapubic pain and bladder dysfunction. Although the pathogenesis of IC is unclear, there is substantial evidence from clinical and basic science studies that growth factor signaling mechanisms may play a role. Growth factors made by the inflamed bladder can potentiate sensory transduction in primary sensory afferents by acting on membrane receptors and ion channels, including K+ channels. These channels are attractive targets for pharmacological modulation of bladder pain and hypersensitivity in IC. Pelvic viscera, including the bladder, receive dual innervation from sensory ganglia arising from two distinct vertebral levels (T13-L2 [TL] and L5-S1 [LS]), and it is thought these populations contribute to different aspects of organ function and sensation. A lack of knowledge regarding how these subpopulations respond to different growth factors or are differentially modulated as a result of changes in K+ curents hampers a complete understanding of bladder afferent function and dysfunction. The hypothesis directing this work is that bladder inflammation induces alterations in the transcriptional expression of Kv channels and biophysical properties of bladder sensory neurons in distinct subpopulations sensory neurons, differentiated in part on their growth factor sensitivity and anatomical distribution. We further propose that these changes may become permanent and result in hyperexcitability contributing to persistent bladder pain. This hypothesis will be tested in a mouse model of IC using molecular and physiological techniques. The experiments are designed such that regardless of the outcome, we will have a better understanding of the phenotype of distinct subpopulations of bladder afferents and potential changes that occur in those afferents in response to inflammation, as well as increased insight into the role played by the primary sensory neuron in the development of persistent bladder pain and dysfunction. PUBLIC HEALTH RELEVANCE: Interstitial cystitis (IC) is a chronic, debilitating urological disorder that is difficult to treat and significantly reduces quality of life. Pain and altered blader function are the most troubling symptoms. The broad objective of this research is to examine the cellular and molecular mechanisms underlying urinary bladder nociception and hypersensitivity. This research will lay a firm groundwork for future studies aimed at developing well-informed and successful pharmacological interventions with a high degree of translational significance for the management of IC pain.