Overactive bladder (OAB) is characterized by sensations of urgency and frequency, implicating ion channels in the afferent system in the etiology of these disorders. Understanding the role afferent pathways have in transmitting signals from the urothelium and urinary bladder smooth muscle to the central nervous system could be crucial in understanding the etiology of lower urinary tract symptoms (LUTS). A number of transient receptor potential channels have been shown to be involved in bladder mechanosensory transduction and nociception. Transient receptor potential cation channel V3 (TRPV3) has been shown to be expressed in the sensory nervous system (dorsal root ganglia, trigeminal ganglia, spinal cord and brain). Its functional interaction with other TRP channels-many of which have been previously documented to be involved in the bladder function and bladder sensory signaling- make it a realistic research target. Urothelial and urinary bladder smooth muscle expression of TRPV3 channel mRNA has been recently documented by others, and our preliminary experiments showed that both mRNA and protein are up-regulated in a mouse model of partial bladder outflow obstruction. We have also provided evidence that TRPV3 modulates urinary bladder smooth muscle contractility and bladder sensory signaling, and that suppression of TRPV3 improves bladder function in animal models of OAB. In vitro testing revealed that a specific TRPV3 antagonist reduced phasic bladder contractions in strips of mouse bladder. We propose to test the hypothesis that TRPV3 channel upregulation could cause increased bladder sensory signaling through 1) potentiation of phasic bladder activity, thus increasing afferent signaling via 'in series'coupled low-threshold mechanoreceptive afferents;and/or;2) through chemical stimulation of intramural bladder sensory nerves and urothelium by neurotransmitters.
In Specific Aim 1, we will determine qualitative and quantitative spacio-temporal patterns of TRPV3 expression. These studies will determine when and where TRPV3 is up-regulated and how this expression compares to the expression of bladder sensory neurotransmitters and neuromediators. Experiments proposed in Specific Aim 2 will determine the influence TRPV3 exerts on phasic bladder activity and bladder sensory signaling.
In Specific Aim 3 we will address the mechanisms by which TRPV3 is involved in regulation of phasic bladder activity and bladder sensory signaling. To gain a better understanding of the role of TRP channels in bladder function, we propose a detailed study of the role of TRPV3 channel alone and in combination with other TRP channels that have been shown to be present and functional in the urinary bladder. Elucidating the interaction between TRPV3 and other TRP channels, could lead to the identification of significant therapeutic targets.
In 2007 in the United States, lower urinary tract symptoms (LUTS) affected 16.5% of adults, resulting in a national cost of $65.9 billion. Despite the magnitude of this health problem, the pathomechanisms that underlie these bothersome symptoms are poorly understood, and over the past decades only limited progress has been made toward improving the quality of life for patients suffering from LUTS. Using innovative, proven research techniques we will study the pathomechanisms leading to LUTS and evaluate the role of a novel ion channel that represents a promising pharmacological target.