The Role of TRPV3 Ion Channel in Bladder Function and Sensory Signaling

描述（由申请人提供）：膀胱过度活动症（OAB）的特征是紧迫感和频率感，表明传入系统中的离子通道与这些疾病的病因有关。了解传入通路在将信号从尿道和膀胱平滑肌传递到中枢神经系统中的作用，对于了解下尿路症状（LUTS）的病因至关重要。许多瞬时受体电位通道已被证明参与膀胱机械感觉传导和伤害感受。瞬时受体电位阳离子通道V3（TRPV 3）已显示在感觉神经系统（背根神经节、三叉神经节、脊髓和脑）中表达。它与其他TRP通道的功能相互作用-其中许多通道先前已被证明参与膀胱功能和膀胱感觉信号传导-使其成为现实的研究目标。TRPV 3通道mRNA的尿路上皮和膀胱平滑肌表达最近已被其他人记录，我们的初步实验表明，在部分膀胱流出道梗阻的小鼠模型中，mRNA和蛋白质均上调。我们还提供了TRPV 3调节膀胱平滑肌收缩性和膀胱感觉信号传导的证据，并且TRPV 3的抑制改善了OAB动物模型中的膀胱功能。体外试验显示，特异性TRPV 3拮抗剂减少小鼠膀胱条中的阶段性膀胱收缩。我们建议测试TRPV 3通道上调可能通过以下方式引起膀胱感觉信号传导增加的假设：1）增强阶段性膀胱活动，从而通过“串联”耦合的低阈值机械感受性传入增加传入信号传导;和/或; 2）通过神经递质对壁内膀胱感觉神经和尿道刺激的化学刺激。在具体目标1中，我们将确定TRPV 3表达的定性和定量时空模式。这些研究将确定TRPV 3何时何地上调，以及这种表达与膀胱感觉神经递质和神经介质的表达相比如何。具体目标2中提出的实验将确定TRPV 3对阶段性膀胱活动和膀胱感觉信号传导的影响。在具体目标3中，我们将讨论TRPV 3参与阶段性膀胱活动和膀胱感觉信号调节的机制。为了更好地了解TRP通道在膀胱功能中的作用，我们提出了一个详细的研究TRPV 3通道单独和与其他TRP通道，已被证明是存在的，并在膀胱功能的作用。阐明TRPV 3和其他TRP通道之间的相互作用，可能会导致识别重要的治疗靶点。

DESCRIPTION (provided by applicant): 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.