Cystitis-Induced Plasticity of Micturition Reflexes

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DESCRIPTION (provided by applicant): Painful Bladder Syndrome (PBS)/Interstitial Cystitis (IC) is a chronic symptom-complex characterized by urinary frequency, urgency, suprapubic, pelvic pain and cystoscopic findings. The hypothesis for this research proposal is that increases in voiding frequency and altered sensation that accompany PBS/IC are due to an alteration in the primary afferent limb of the micturition reflex and, in part, to an alteration in interneuronal mechanisms in the spinal cord. Increased urinary frequency with cystitis may also be due to an alteration in the efferent limb of the micturition reflex. The combination of these changes facilitates a spinal reflex pathway to the urinary bladder by altering synaptic transmission at the interneuronal level and to the pelvic ganglia. The contribution of nerve growth factor (NGF) and NGF/receptor tyrosine kinase (TrkA) interactions to inflammatory-induced changes in urinary bladder function, neurochemical plasticity in lower urinary tract (LUT) pathways and central organization of LUT reflexes has been defined. The proposed aims provide mechanistic insight into inflammation-induced changes in neural control of micturition reflexes using the CYP rat model of urinary bladder inflammation, a novel, chronic overexpressing NGF mouse line (UPII-NGFv2) and a multidisciplinary experimental approach. Aim 1: To mimic the environment of chronic bladder inflammation and PBS/IC, mice with chronic overexpression of NGF in the urothelium (UPII-NGFv2) will be used to determine the role that NGF plays in mediating functional, neurochemical and organizational plasticity of bladder reflexes using conscious cystometry, immunohistochemistry and intracellular recording techniques. Whether neural plasticity is secondary to changes in neurochemical phenotype of the micturition reflex will be determined. Aim 2: p75NTR and Trk receptors interact to regulate the affinity of TrkA receptor for its cognate ligand, NGF. The involvement of Trk versus p75NTR mediated signaling in LUT pathways in control, CYP-treated rodents, UPII-NGFv2 and backcrossed wildtype mice will be determined. These studies will use pharmacological tools to block NGF/TrkA versus NGF/p75 signaling. Aim 3: The biological roles of neurotrophin-induced signals are unknown especially in the LUT. The temporal activation of ERK1/2, ERK5 and Akt in lumbosacral spinal cord, DRG and urinary bladder after CYP-induced cystitis in rats and in UPII-NGFv2 mice will be determined. The neurochemical properties and the organization of spinal micturition reflexes after administration of ERK or PI3K inhibitors will be determined. These studies may provide insights into potential targets and therapeutic interventions for PBS/IC in the future. PUBLIC HEALTH RELEVANCE Painful Bladder Syndrome (PBS)/Interstitial Cystitis (IC) is a chronic symptom-complex characterized by urinary frequency, urgency, suprapubic, pelvic pain and cystoscopic findings. Inflammation-induced expression of growth factors (e.g. nerve growth factor, NGF) in the urinary bladder or urine of women with PBS/IC and subsequent interactions with the central and peripheral nervous system may contribute to these symptoms. These studies will determine how NGF interactions with membrane bound receptors and activation of cellular signaling events could contribute to urinary bladder dysfunction and changes in sensory processing. These studies will contribute to the understanding of inflammation-induced changes in chronic bladder inflammation and may provide insights into potential targets and therapeutic interventions for PBS/IC in the future.