Interstitial cystitis (IC) is a chronic inflammatory bladder disease syndrome characterized by urinary frequency, urgency, suprapubic and pelvic pain. Although the etiology and pathogenesis of IC are unknown, numerous theories including; infection, autoimmune disorder, toxic urinary agents, deficiency in bladder wall lining and neurogenic causes have been proposed. Pituitary adenylate cyclase activating polypeptide (PACAP) exerts diverse and prevalent roles in the lower urinary tract (LUT). Sensory fibers expressing PACAP have been identified in the bladder wall and in suburothelial plexuses, PACAP expression in the micturition reflex pathway is upregulated following chronic cystitis and pharmacological agents that block PACAP receptor function reduce bladder overactivity after cystitis. PACAP expression can be regulated by neurotrophins; conversely, recent studies have also suggested that PACAP may regulate neurotrophin receptor tyrosine kinase expression and activation. Cystitis markedly alters the profile of neurotrophin expression in bladder tissues. Thus, the resulting changes in target organ growth factor levels may drive the neurochemical and functional plasticity in the micturition pathway with cystitis. The overall hypothesis for our work is that pain and micturition dysfunction in IC involves an alteration in bladder smooth muscle, urothelium and sensory physiology. The central hypothesis is that the VIPIPACAP system is a prominent modulator of bladder sensation and function and the inflammation-induced changes in neurotrophic factors and/or neural activity arising in the bladder alter PACAP/PACAP receptor expression in LUT to mediate altered micturition function in IC. The following three aims test these hypotheses. 1). To characterize PACAP and PACAP receptor expression in urothelium, bladder smooth muscle and bladder afferent cells in the lumbosacral DRG; 2). To establish the functional relationships between PACAP and neurotrophin systems in the normal micturition reflex pathway and after cystitis.; 3). To evaluate the physiological roles of PACAP and neurotrophins in the micturition reflex pathway using PACAP knockout mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK065989-03
Application #
6932294
Study Section
Special Emphasis Panel (ZRG1-UROL (51))
Program Officer
Mullins, Christopher V
Project Start
2003-09-30
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$287,289
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
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
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
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; Peterson, Abbey; Erickson, Cuixia Shi et al. (2014) Social stress induces changes in urinary bladder function, bladder NGF content, and generalized bladder inflammation in mice. Am J Physiol Regul Integr Comp Physiol 307:R893-900
Dugan, C; Malley, S; Arms, L et al. (2014) Role of c-Jun N-terminal kinase (JNK) activation in micturition reflexes in cyclophosphamide (CYP)-induced cystitis in female rats. J Mol Neurosci 54:360-9
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
Zvarova, K; Herrera, G M; May, V et al. (2014) Cocaine- and amphetamine-regulated transcript peptide (CARTp): distribution and function in rat urinary bladder. J Mol Neurosci 54:351-9

Showing the most recent 10 out of 57 publications