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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060481-08
Application #
8288241
Study Section
Special Emphasis Panel (ZRG1-RUS-B (11))
Program Officer
Hoshizaki, Deborah K
Project Start
2001-12-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$320,824
Indirect Cost
$107,652
Name
University of Vermont & St Agric College
Department
Neurology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Girard, Beatrice; Peterson, Abbey; Malley, Susan et al. (2016) Accelerated onset of the vesicovesical reflex in postnatal NGF-OE mice and the role of neuropeptides. Exp Neurol 285:110-125
Merrill, Liana; Gonzalez, Eric J; Girard, Beatrice M et al. (2016) Receptors, channels, and signalling in the urothelial sensory system in the bladder. Nat Rev Urol 13:193-204
Girard, Beatrice M; Malley, Susan; May, Victor et al. (2016) Effects of CYP-Induced Cystitis on Growth Factors and Associated Receptor Expression in Micturition Pathways in Mice with Chronic Overexpression of NGF in Urothelium. J Mol Neurosci 59:531-43
Gonzalez, Eric J; Peterson, Abbey; Malley, Susan et al. (2015) The effects of tempol on cyclophosphamide-induced oxidative stress in rat micturition reflexes. ScientificWorldJournal 2015:545048
Vizzard, Margaret A (2015) Pannexins: the 'nexus' between urothelium ATP production and extracellular release. J Physiol 593:1759-60
Mingin, Gerald C; Heppner, Thomas J; Tykocki, Nathan R et al. (2015) Social stress in mice induces urinary bladder overactivity and increases TRPV1 channel-dependent afferent nerve activity. Am J Physiol Regul Integr Comp Physiol 309:R629-38
Merrill, Liana; Vizzard, Margaret A (2014) Intravesical TRPV4 blockade reduces repeated variate stress-induced bladder dysfunction by increasing bladder capacity and decreasing voiding frequency in male rats. Am J Physiol Regul Integr Comp Physiol 307:R471-80
Gonzalez, Eric J; Arms, Lauren; Vizzard, Margaret A (2014) The role(s) of cytokines/chemokines in urinary bladder inflammation and dysfunction. Biomed Res Int 2014:120525
Missig, Galen; Roman, Carolyn W; Vizzard, Margaret A et al. (2014) Parabrachial nucleus (PBn) pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the amygdala: implication for the sensory and behavioral effects of pain. Neuropharmacology 86:38-48
Vizzard, Margaret A (2014) New modulatory pathways in micturition reflex function. J Urol 192:638-9

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