Patients with inflammatory bowel disease often experience increased sensory responsiveness in the urinary bladder reflecting neurogenic bladder overactivity. This visceral symptom overlap involves neuronal cross-activation in the dorsal root ganglia (DRG) where the bladder afferent neurons are sensitized. The long- term goal of this project has been to understand the complex neuronal interaction between colonic and bladder sensory pathways, and to identify mediators that regulate bladder sensory hypersensitivity as a result of colitis. Our publications and preliminary data have shown that the brain-derived neurotrophic factor (BDNF)/TrkB system has a prominent role in the regulation of bladder activity. In this renewal application, we hypothesize that the phospholipase C-gamma (PLC?)-calcium (Ca2+) pathways are unique downstream of the increased endogenous BDNF/TrkB in bladder afferent neurons, and play an integral role in bladder afferent activation by Ca2+-dependent transcriptional and posttranslational regulation of neuroactive compounds during colitis. To address this hypothesis, three interrelated Specific Aims are proposed to examine the regulatory mechanism and the targets of the PLC?-Ca2+ pathways including Ca2+/calmodulin-dependent protein kinase (CaMK)II, cAMP-response element binding protein (CREB), calcitonin gene-related peptide (CGRP), and cerebellin 1 precursor (Cbln1) in bladder afferent neurons before and during colitis.
In AIM 1, we will characterize the expression profiles of a series of components regulating Ca2+ mobilization (phospholipase C?, InsP3R-1, voltage-gated Ca2+ channels predominantly the N-type channel Cav2.2) and Ca2+-dependent neuronal activation (CaMKII and CREB) in bladder afferent neurons at 7 days and 21 days of colitis. This will be done at the molecular (mRNA and protein) and functional (intracellular Ca2+ recording and electrophysiology) levels.
In AIM 2, we will examine the regulatory mechanism by which the PLC?-Ca2+ pathways are activated by endogenous BDNF in bladder afferent neurons during colitis. For this purpose, we will use a newly developed yet well-characterized BDNF+/- rat strain.
In AIM 3, we will combine molecular biological, pharmacological, neurochemical, and behavioral tests to examine the functional role of the BDNF-Ca2+ axis in bladder hyperactivity during colitis. We will characterize how the Ca2+-dependent pathways are involved in CGRP and Cbln1 expression, and how they regulate bladder afferent neuronal hyperactivity and modulate bladder micturition parameters during colitis. For studies proposed above, we will utilize a variety of in vivo (transgenic animals, intrathecal delivery of drugs, behavioral studies and ex vivo/in vitro (DRG explants, isolated DRG neuron culture and transfection) systems. The localized colonic inflammation will be induced by intracolonic instillation of tri-nitrobenzene sulfonic acid (TNBS) in rat. As several small molecule antagonists of the Ca2+ pathways are under clinical trials in treatment of other pain symptoms, we anticipate that the current systematic studies will provide insights into forming therapeutic strategies in the treatment of visceral hypersensitivity.

Public Health Relevance

Co-existence of gut and bladder symptoms is a very common occurrence in humans. This research project focuses on the molecular mechanism underlying the increased responsiveness in the urinary bladder during colitis. Specifically, the project will investigate the role of brain-derived neurotrophic factor (BDNF)-mediated phospholipase C-gamma (PLC?)-calcium pathways in the activation of bladder afferent neurons and in bladder hyperactivity as a result of colitis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
Schools of Medicine
United States
Zip Code
Qiao, Li-Ya; Xia, Chunmei; Shen, Shanwei et al. (2018) Urinary bladder organ hypertrophy is partially regulated by Akt1-mediated protein synthesis pathway. Life Sci 201:63-71
Shen, Shanwei; Al-Thumairy, Hamad W; Hashmi, Fiza et al. (2017) Regulation of transient receptor potential cation channel subfamily V1 protein synthesis by the phosphoinositide 3-kinase/Akt pathway in colonic hypersensitivity. Exp Neurol 295:104-115
Hashmi, Fiza; Liu, Miao; Shen, Shanwei et al. (2016) EXPRESS: Phospholipase C gamma mediates endogenous brain-derived neurotrophic factor - regulated calcitonin gene-related peptide expression in colitis - induced visceral pain. Mol Pain 12:
Qiao, L Y; Shen, S; Liu, M et al. (2016) Inflammation and activity augment brain-derived neurotrophic factor peripheral release. Neuroscience 318:114-21
Xia, Chunmei; Shen, Shanwei; Hashmi, Fiza et al. (2016) Colitis-induced bladder afferent neuronal activation is regulated by BDNF through PLC? pathway. Exp Neurol 285:126-135
Shen, Shanwei; Xia, Chun-Mei; Qiao, Li-Ya (2015) The urinary bladder of spontaneously hypertensive rat demonstrates bladder hypertrophy, inflammation, and fibrosis but not hyperplasia. Life Sci 121:22-7
Liu, Miao; Shen, Shanwei; Kendig, Derek M et al. (2015) Inhibition of NMDAR reduces bladder hypertrophy and improves bladder function in cyclophosphamide induced cystitis. J Urol 193:1676-83
Liu, Miao; Kay, Jarren C; Shen, Shanwei et al. (2015) Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord via PLC?, PKC, and PI3K/Akt pathways during colitis. J Neuroinflammation 12:151
Qiao, Li-Ya (2014) Neurotrophin signaling and visceral hypersensitivity. Front Biol (Beijing) 9:216-224
Qiao, Zhongwei; Xia, Chunmei; Shen, Shanwei et al. (2014) Suppression of the PI3K pathway in vivo reduces cystitis-induced bladder hypertrophy and restores bladder capacity examined by magnetic resonance imaging. PLoS One 9:e114536

Showing the most recent 10 out of 21 publications