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

TRPV3 离子通道在膀胱功能和感觉信号传导中的作用

• 批准号: 8851245
• 负责人: Peter Zvara
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-06 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851245
• 关键词: Acetic Acids; Address; Adult; Affect; Afferent Pathways; Animal Model; Animals; Bladder; Bladder Urothelium; Brain; C Fiber; Capsaicin; Cations; Cellular Mechanotransduction; Chemical Stimulation; Chemosensitization; Complex; Control Animal; Coupled; Development; Disease; Esthesia; Etiology; Family; Family member; Frequencies; Health; Heating; Infusion procedures; Intervention; Ion Channel; Knockout Mice; Knowledge; Lead; Mechanoreceptors; Messenger RNA; Modeling; Mus; Muscle function; Myography; Nerve; Nervous system structure; Neuraxis; Neuropeptides; Neurotransmitters; Nociception; Obstruction; Organ; Overactive Bladder; Pain; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Physiological; Play; Proteins; Quality of life; Regulation; Research; Research Technics; Role; Sensory; Series; Signal Transduction; Signaling Molecule; Skin; Smooth Muscle; Spinal Cord; Spinal Ganglia; Structure of trigeminal ganglion; Symptoms; System; Targeted Research; Testing; Therapeutic; Therapeutic Effect; United States; Up-Regulation; Urothelium; Vanilloid; afferent nerve; awake; clinically relevant; cost; detrusor muscle; improved; in vitro testing; in vivo; innovation; insight; intravesical; keratinocyte; lower urinary tract symptoms; member; mouse model; neurotransmitter release; novel; receptor; research study; response; sensor; therapeutic target

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.

描述（由申请人提供）：膀胱过动症（OAB）的特征是急迫感和频率感，暗示传入系统中的离子通道与这些疾病的病因有关。了解传入通路在尿路上皮和膀胱平滑肌向中枢神经系统传递信号中的作用，对于理解下尿路症状（LUTS）的病因至关重要。一些瞬时受体电位通道已被证明参与膀胱机械感觉转导和伤害感受。瞬时受体电位阳离子通道V3 （TRPV3）已被证实在感觉神经系统（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-其中许多已被记录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。TRPV3通道mRNA在尿路上皮和膀胱平滑肌的表达最近已被其他人证实，我们的初步实验表明，在部分膀胱流出梗阻小鼠模型中，mRNA和蛋白均上调。我们也提供了证据表明，TRPV3调节膀胱平滑肌收缩和膀胱感觉信号，并且在OAB动物模型中，抑制TRPV3可改善膀胱功能。体外实验显示，一种特异性的TRPV3拮抗剂可减少小鼠膀胱条状的相膀胱收缩。我们提出验证TRPV3通道上调可能通过以下途径导致膀胱感觉信号增加的假设：1)膀胱相活动增强，从而通过“串联”耦合低阈值机械感受传入信号增加；和/或;2)通过神经递质化学刺激膀胱内感觉神经和尿路上皮。在Specific Aim 1中，我们将定性和定量地确定TRPV3表达的时空模式。这些研究将确定TRPV3何时何地上调，以及其表达与膀胱感觉神经递质和神经介质的表达如何比较。在Specific Aim 2中提出的实验将确定TRPV3对相膀胱活动和膀胱感觉信号的影响。在Specific Aim 3中，我们将探讨TRPV3参与调节相膀胱活动和膀胱感觉信号的机制。为了更好地了解TRP通道在膀胱功能中的作用，我们建议详细研究TRPV3通道单独以及与其他已被证明存在并在膀胱中起作用的TRP通道联合的作用。阐明TRPV3与其他TRP通道之间的相互作用，可能有助于确定重要的治疗靶点。