There are a number of childhood voiding dysfunctions that may be attributable to abnormal postnatal maturation of voiding reflexes. Recent studies have shown a strong correlation between childhood lower urinary tract (LUT) dysfunction and adult overactive bladder. Thus, understanding the factors that regulate the neural control of voiding function during the postnatal period may provide insight into childhood and adult voiding dysfunction. Furthermore, injuries or diseases of the adult nervous system can lead to the reemergence of primitive functions that were prominent early in development but then were suppressed during neural maturation. Therefore, developmental studies of micturition reflex pathways are likely to provide key insights into the mechanisms underlying neurogenic disorders of urinary bladder function in adults. The central hypothesis of this proposal is that changes in both the central nervous system (CNS) and peripheral nervous system (PNS) drive micturition reflex maturation. Marked changes in the neural control of voiding function that occur during early postnatal development may be mediated by multiple factors, including upregulation of mature supraspinal mechanisms (corticotropin releasing factor, CRF/CRF receptor system) and changes in neuron and target organ (postganglionic neuronyenurinary bladder) interactions. In this competitive renewal application, we propose aims that will provide further mechanistic insight into developmental-induced changes in the neural control of micturition reflexes using a multidisciplinary experimental approach involving a rat model as well as a novel, chronic overexpressing nerve growth factor (NGF) mouse line (UPII-NGFv2).
The aims of this proposal are: (1) to characterize the CRF/CRF receptor system in the lumbosacral spinal cord and to define the function of the CRF/CRF receptor system in LUT pathways as a function of development;(2) to determine the mechanisms underlying an accelerated development of mature voiding function in UPII-NGFv2 mice;(3) to define the functional properties of bladder postganglionic cells in the major pelvic ganglion (MPG) during development, the underlying channel properties that contribute to the diversity of electrophysiological properties in the adult and the contribution of urinary bladder NGF to these properties.
Project Narrative There are a number of childhood voiding dysfunctions that may be attributable to abnormal postnatal maturation of voiding reflexes. Recent studies have shown a strong correlation between childhood lower urinary tract dysfunction and adult overactive bladder. Thus, understanding the factors that regulate the neural control of voiding function during the postnatal period may provide insight into childhood and adult voiding dysfunction. Furthermore, injuries or diseases of the adult nervous system can lead to the reemergence of primitive functions that were prominent early in development but then were suppressed during neural maturation. Therefore, developmental studies of micturition reflex pathways are likely to provide key insights into the mechanisms underlying neurogenic disorders of urinary bladder function in adults. These studies will focus on the development of the prominent neurotransmitter/receptor system in descending spinal pathways and changes and mechanisms involved in neuron and target organ (i.e., postganglionic neuronyenurinary bladder) interactions that underlie maturation of voiding function. It is anticipated that these studies will provide insights into potential targets and therapeutic interventions for childhood and adult voiding dysfunctions.
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