Electrophysiologic, pharmacologic and neurochemical techniques will be used to examine the mechanisms underlying the neural detection of noxious stimuli in the lower urinary tract. We areparticularly interested in identifying the chemical mediators which sensitize bladder, nociceptors and how these chemical mediators alter ion channels in afferent neurons and thereby change afferent receptor excitability. We will also examine changes in afferent neurons induced by chronic pathological conditions that result in bladder irritation and hyperactivity. Several hypotheses will be tested: (1) Several subtypes of nociceptors are present in the bladder wall and these subtypes exhibit distinct electrophysiologic properties arid-distinct receptive/signaling mechanisms, (2) Acute sensitization of bladder nociceptors involves a change in several membrane ion channels including: tetrodotoxin-resistant Na+ channels, yanilloid receptors (VRl) which are sensitive to capsaicin, ATP-sensitive purinergic receptors, fast activation R+ channels and acid sensitive cation channels (ASIC), (3) Chronic pathological conditions of the lower urinary tract alter the expression of ion channels or neurotransmitter mechanisms in afferent neurons. This effect may be mediated by neurotrophic factors released within the bladder, (4) Bidirectional chemical communication between the urothelium and adjacent nerves plays a role in sensory mechanisms as well as in epithelial cell function in the urinary tract. The long-term objectives of the research program are to understand the mechanisms by which irritating or tissue-injuring stimuli are detected and processed by the nervous system and in turn modulate urinary tract function. The contribution of the urothelium to sensory processing will receive particular attention. The ultimate goal is to identify new molecular targets for drug therapy of bladder pain. PERFORMANCE SfTE(S) (organization, dry, state) Department of Pharmacology, Medical School, University of Pittsburgh Pittsburgh, PA, 15261 KEY PERSONNEL See instructions on Page 11. Use continuation pages as neededto provide the required information in the format shown below. Name Organization Role on Project William C. de Groat University of Pittsburgh PI Adrian Sculptoreanu """""""" """""""" Res. Associate Alyssa Hawranko Naoki Yoshimura """""""" """""""" Res. Ass. Prof. Kyu-Sung Lee """""""" """""""" Res. Associate Yao-Chi Chuang """""""" """""""" Visiting Ass. Prof. Jon Beckel """""""" """""""" Res. Assistant PHS 398 (Rev. 4/98) Page 2 BB Number pages consecutivelyat the bottomthroughout the application. Dorjoj use suffixes suchas 3a, 3b. cc Principal Investigator/Program Director (Last, first, middle): de Groat, William C. Type the name of the principal investigator/proj^^ director at the top of each printed page and eachJ^tinuation page. (Fortype specifications, see instructions on page 6.) ^Ir ^P ? u- RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page..: :.. ; 1 Description,

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK049430-13
Application #
7198072
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mullins, Christopher V
Project Start
1994-09-30
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
13
Fiscal Year
2007
Total Cost
$335,591
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
de Groat, William C; Yoshimura, Naoki (2012) Plasticity in reflex pathways to the lower urinary tract following spinal cord injury. Exp Neurol 235:123-32
Artim, Debra E; Kullmann, F Aura; Daugherty, Stephanie L et al. (2011) Developmental and spinal cord injury-induced changes in nitric oxide-mediated inhibition in rat urinary bladder. Neurourol Urodyn 30:1666-74
Cheng, Chen-Li; de Groat, William C (2011) Effect of ovariectomy on external urethral sphincter activity in anesthetized female rats. J Urol 186:334-40
Kullmann, F Aura; Downs, Thomas R; Artim, Debra E et al. (2011) Urothelial beta-3 adrenergic receptors in the rat bladder. Neurourol Urodyn 30:144-50
Kanai, Anthony; Zabbarova, Irina; Ikeda, Youko et al. (2011) Sophisticated models and methods for studying neurogenic bladder dysfunction. Neurourol Urodyn 30:658-67
Artim, D E; Bazely, F; Daugherty, S L et al. (2011) Nitro-oleic acid targets transient receptor potential (TRP) channels in capsaicin sensitive afferent nerves of rat urinary bladder. Exp Neurol 232:90-9
Limberg, Brian J; Andersson, Karl-Erik; Aura Kullmann, F et al. (2010) ?-Adrenergic receptor subtype expression in myocyte and non-myocyte cells in human female bladder. Cell Tissue Res 342:295-306
Buyuknacar, Hacer S G; Gocmen, Cemil; de Groat, William C et al. (2010) Differential effect of L-cysteine in isolated whole-bladder preparations from neonatal and adult rats. J Pharmacol Exp Ther 333:228-35
de Groat, William C; Yoshimura, Naoki (2010) Changes in afferent activity after spinal cord injury. Neurourol Urodyn 29:63-76
Yu, Yongbei; de Groat, William C (2010) Effects of stimulation of muscarinic receptors on bladder afferent nerves in the in vitro bladder-pelvic afferent nerve preparation of the rat. Brain Res 1361:43-53

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