Traditionally sensory signaling in the urinary bladder has been attributed to direct activation of bladder afferents. New findings have highlighted urinary bladder urothelial cells as key players in the transduction of sensory events. We have shown that urothelial cells exhibit a number of """"""""neuron-like"""""""" properties (including expression of sensor molecules that allow them to respond to chemical/thermal/mechanical stimuli and to release chemical mediators) making it likely that urothelial cells communicate """"""""directly"""""""" with bladder nerves or indirectly via urothelial cell-cell interactions. Urothelial cells are constantly exposed to various forms of mechanical stimuli, yet the mechanisms by which these cells respond are not well defined. Mechanical forces are thought to """"""""initiate"""""""" a series of signaling events (calcium waves) throughout the urothelium. In turn, the accompanying release of chemical factors induced by mechanical stimuli could activate urothelial cell surface receptors and amplify the signal within and adjacent to the urothelial cell. Although these data suggest that urothelial cells play an important role in cell-cell signaling, this is a relatively unexplored area with little information known about the mechanism for sensory transduction or the mode of communication between cells. Using a multidisciplinary approach involving pharmacology, siRNA, transmitter release, patch clamp and novel imaging techniques, our goals are to evaluate how urothelial cells receive and integrate multiple stimuli.
Specific Aim 1 will characterize urothelial cell mechanosensors and their mechano-transduction pathways. Evidence has shown that TRPV1 is essential for mechanically-evoked purinergic signaling by the urothelium, yet the mechanisms by which urothelial cells respond to mechanical forces are not well defined.
This aim i n part will examine the involvement of TRP channels in urothelial mechanotransduction.
Specific Aim 2 will evaluate the mechanism by which various transmitters are released from urothelial cells.
The aim will utilize imaging with fluorescent dyes to study how chemical and physical stimuli stimulate movement and release of transmitters from vesicles in urothelial cells.
Specific Aim 3 will elucidate the responses evoked by mechano-stimulation in coupled and adjacent cellular targets.
This aim will utilize conditions of increasing complexity (signaling within a single cell;urothelial-neuron co-cultures and intact tissue) to examine mechanisms for cell-cell interactions. These imaging methods will enable us to evaluate urothelial-cell signaling between different regions of the bladder as well as within the urothelial layers. Results from these studies will help us to understand how urothelial cells receive and integrate multiple stimuli thus providing an important """"""""link"""""""" in the transfer of information from the urinary bladder to the nervous system. Understanding these mechanisms may provide important insight for the identification of novel targets for the future clinical management of bladder dysfunctions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-RUS-A (04))
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Mullins, Christopher V
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Kullmann, F Aura; Beckel, Jonathan M; McDonnell, Bronagh et al. (2018) Involvement of TRPM4 in detrusor overactivity following spinal cord transection in mice. Naunyn Schmiedebergs Arch Pharmacol 391:1191-1202
Birder, Lori A; Kullmann, F Aura (2018) Role of neurogenic inflammation in local communication in the visceral mucosa. Semin Immunopathol 40:261-279
Kullmann, F Aura; McDonnell, Bronagh M; Wolf-Johnston, Amanda S et al. (2018) Inflammation and Tissue Remodeling in the Bladder and Urethra in Feline Interstitial Cystitis. Front Syst Neurosci 12:13
Kullmann, F A; Chang, H H; Gauthier, C et al. (2018) Serotonergic paraneurones in the female mouse urethral epithelium and their potential role in peripheral sensory information processing. Acta Physiol (Oxf) 222:
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Charrua, Ana; Pinto, Rui; Birder, Lori Ann et al. (2015) Sympathetic nervous system and chronic bladder pain: a new tune for an old song. Transl Androl Urol 4:534-42
Kullmann, Florenta Aura; Birder, Lori Ann; Andersson, Karl-Erik (2015) Translational Research and Functional Changes in Voiding Function in Older Adults. Clin Geriatr Med 31:535-48

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