Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure or discomfort perceived to be bladder related with at least one urinary symptom. The impact of BPS/IC on quality of life and economic burden are enormous. Over the life of this grant, we have hypothesized that pain associated with BPS/IC involves an alteration of visceral sensation/bladder sensory physiology. Changes in visceral sensation may be mediated, in part, by inflammatory changes in the urinary bladder including nerve growth factor (NGF). Monoclonal antibody treatment that specifically inhibits NGF in patients with BPS/IC demonstrates proof of concept;however, clinical trials have halted enrollment due to severe side effects. The need for additional targets beyond NGF is clear. With this competitive renewal application, we propose aims that will provide mechanistic insight into additional NGF-mediated pleiotropic changes that contribute to urinary bladder hyperreflexia and pelvic hypersensitivity in a novel transgenic mouse model of chronic NGF overexpression (NGF-OE) using the urothelium-specific uroplakin II promoter that was characterized during the last funding cycle. The working hypothesis is that increases in urinary frequency and altered sensation that accompany BPS/IC are due to an alteration in the expression, function and interactions of neurochemical mediators and the sensory transducer, transient receptor potential (TRPV) family member TRPV4, in the sensory limb of the urinary bladder reflex. These studies examine the contributions of and interactions between the neuropeptide, PACAP, and receptor PAC1 and TRPV4 to increased voiding frequency and somatic sensitivity in NGF-OE mice.
Aim 1 : We hypothesize that NGF overexpression exhibited in urothelium and lumbosacral dorsal root ganglia (DRG) of the NGF-OE mouse model induces upregulation of the sensory transducer, TRPV4, in bladder afferent cells in DRG and in urothelial cells of the urinary bladder. We hypothesize that tissue-specific expression of TRPV4, in sensory components (urothelium, DRG) of the micturition reflex contributes to urinary bladder hyperreflexia and pelvic hypersensitivity in NGF-OE mice.
Aim 2 : We hypothesize that interactions between TRPV4 and PACAP/PAC1 may represent a novel mechanism by which PACAP/PAC1 signaling activates phospholipase C and inositol triphosphate to sensitize TRPV4-mediated changes in voiding behavior and painful sensation. Furthermore, we hypothesize that PAC1 and TRPV4 are co-expressed in bladder afferent DRG and urothelial cells. We will use a multidisciplinary approach including anatomical, biochemical, molecular, electrophysiological, and functional methodologies and a novel ex vivo peripheral nerve recording approach to address these aims. Results will provide key insights into new targets with therapeutic potential to improve urinary bladder function and visceral sensation.

Public Health Relevance

Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome with at least one urinary symptom. The impact of BPS/IC on quality of life and the resulting economic burden are enormous. The working hypothesis for this research proposal is that increases in urinary frequency and altered sensation that accompany BPS/IC are due to an alteration in the expression, function and interactions of neurochemical mediators and the sensory transducer, TRPV4, in the sensory limb of the urinary bladder reflex. The results of these experiments will provide key, new insights into novel targets with therapeutic potential.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051369-17
Application #
8642172
Study Section
(UGPP)
Program Officer
Bavendam, Tamara G
Project Start
1996-07-29
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Burlington
State
VT
Country
United States
Zip Code
05405
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
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
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; 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
Gonzalez, Eric J; Heppner, Thomas J; Nelson, Mark T et al. (2016) Purinergic signalling underlies transforming growth factor-?-mediated bladder afferent nerve hyperexcitability. J Physiol 594:3575-88
Bishop, James H; Fox, James R; Maple, Rhonda et al. (2016) Ultrasound Evaluation of the Combined Effects of Thoracolumbar Fascia Injury and Movement Restriction in a Porcine Model. PLoS One 11:e0147393
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

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