Plasticity in the sensory innervation of the urinary bladder underlies the pain accompanying inflammatory states, such as interstitial cystitis. Our recent studies on bladder sensory neurons and urothelium have revealed novel and powerful actions of estrogens on signaling processes in both types of ceils. These studies have also indicated the importance of defining how estrogens interact with other neuroactive molecules integral to inflammatory changes, such as nerve growth factor and ATP. Together, this work raises the possibility of identifying new pharmacological strategies for targeting and controlling plasticity in this system and hence reducing the associated pain. In this project we propose a comprehensive group of studies on bladder sensory neurons and urothelial cells to further explore the role of estrogens in modulating the activity of bladder sensory neurons and urothelium. Our goal is to identify the cellular mechanisms by which estrogens influence of the plasticity of bladder sensory pathways after acute and chronic inflammation. The major aims are: (1) To understand the mechanism by which estrogens affect the detection of noxious stimuli by the bladder, under normal and inflamed conditions; (2) To determine how estrogens affect the modulation of nociceptive signaling by other factors. To achieve these aims the project will combine an array of experimental approaches, including cell signaling studies, cultures of adult bladder sensory neurons, immunofluorescence and image analysis, patch clamp electrophysiology and a novel neuron-urothelium co-culture system. These studies will lead to advances in our understanding of estrogen actions on bladder afferent innervation, especially bladder nociception, and will provide important insights into bladder dysfunction, especially conditions involving inflammation. This may assist with the development of new strategies to counteract painful sequelae of bladder inflammation or blocking spread of pain to other pelvic viscera.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK069351-01A1
Application #
6965200
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
2005-09-01
Project End
2010-06-30
Budget Start
2005-09-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$184,500
Indirect Cost
Name
University of Sydney
Department
Type
DUNS #
752389338
City
Sydney
State
Country
Australia
Zip Code
2006
Forrest, Shelley L; Osborne, Peregrine B; Keast, Janet R (2014) Characterization of axons expressing the artemin receptor in the female rat urinary bladder: a comparison with other major neuronal populations. J Comp Neurol 522:3900-27
O'Mullane, Lauren M; Keast, Janet R; Osborne, Peregrine B (2013) Co-cultures provide a new tool to probe communication between adult sensory neurons and urothelium. J Urol 190:737-45
Keast, Janet R; Forrest, Shelley L; Osborne, Peregrine B (2010) Sciatic nerve injury in adult rats causes distinct changes in the central projections of sensory neurons expressing different glial cell line-derived neurotrophic factor family receptors. J Comp Neurol 518:3024-45
Cheng, Ying; Keast, Janet R (2009) Effects of estrogens and bladder inflammation on mitogen-activated protein kinases in lumbosacral dorsal root ganglia from adult female rats. BMC Neurosci 10:156
Forrest, Shelley L; Keast, Janet R (2008) Expression of receptors for glial cell line-derived neurotrophic factor family ligands in sacral spinal cord reveals separate targets of pelvic afferent fibers. J Comp Neurol 506:989-1002
Xu, Shenghong; Cheng, Ying; Keast, Janet R et al. (2008) 17beta-estradiol activates estrogen receptor beta-signalling and inhibits transient receptor potential vanilloid receptor 1 activation by capsaicin in adult rat nociceptor neurons. Endocrinology 149:5540-8
Purves-Tyson, T D; Arshi, M S; Handelsman, D J et al. (2007) Androgen and estrogen receptor-mediated mechanisms of testosterone action in male rat pelvic autonomic ganglia. Neuroscience 148:92-104