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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051369-12
Application #
7664330
Study Section
Special Emphasis Panel (ZRG1-RUS-B (11))
Program Officer
Mullins, Christopher V
Project Start
1996-07-29
Project End
2013-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
12
Fiscal Year
2009
Total Cost
$319,813
Indirect Cost
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
Ojala, Jacqueline; Tooke, Katharine; Hsiang, Harrison et al. (2018) PACAP/PAC1 Expression and Function in Micturition Pathways. J Mol Neurosci :
Ryu, Jae Cheon; Tooke, Katharine; Malley, Susan E et al. (2018) Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest 128:1772-1786
Heppner, Thomas J; Hennig, Grant W; Nelson, Mark T et al. (2018) PACAP38-Mediated Bladder Afferent Nerve Activity Hyperexcitability and Ca2+ Activity in Urothelial Cells from Mice. J Mol Neurosci :
Girard, Beatrice M; Tooke, Katharine; Vizzard, Margaret A (2017) PACAP/Receptor System in Urinary Bladder Dysfunction and Pelvic Pain Following Urinary Bladder Inflammation or Stress. Front Syst Neurosci 11:90
Heppner, Thomas J; Hennig, Grant W; Nelson, Mark T et al. (2017) Rhythmic Calcium Events in the Lamina Propria Network of the Urinary Bladder of Rat Pups. Front Syst Neurosci 11:87
Missig, Galen; Mei, Linda; Vizzard, Margaret A et al. (2017) Parabrachial Pituitary Adenylate Cyclase-Activating Polypeptide Activation of Amygdala Endosomal Extracellular Signal-Regulated Kinase Signaling Regulates the Emotional Component of Pain. Biol Psychiatry 81:671-682
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
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
Girard, Beatrice M; Malley, Susan E; Mathews, Morgan M et al. (2016) Intravesical PAC1 Receptor Antagonist, PACAP(6-38), Reduces Urinary Bladder Frequency and Pelvic Sensitivity in NGF-OE Mice. J Mol Neurosci 59:290-9

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