The role of HVA alpha1E Ca2+ channel subunit in micturition reflex pathways

HVA α1E Ca2 通道亚基在排尿反射通路中的作用

• 批准号: 7985155
• 负责人: Katarina Zvarova
• 金额: $ 5.4万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-20 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985155
• 关键词: Address; Adenosine Triphosphate; Affect; Afferent Neurons; Animals; Applications Grants; Bladder; Bladder Urothelium; Calcium; Calcium Channel; Cell membrane; Cells; Data; Electrophysiology (science); Equilibrium; Functional disorder; Goals; In Vitro; Knowledge; Limb structure; Lower urinary tract; Mediating; Mediator of activation protein; Medical; Micturition Reflex; Molecular Biology; Muscle Contraction; Nerve; Neuronal Plasticity; Nitric Oxide; Pathway interactions; Pattern; Physiological; Play; Property; Rattus; Regulation; Research; Role; Sensory; Signal Transduction; Smooth Muscle; Spinal Cord; Spinal Ganglia; Techniques; Tissues; Urination; Urothelium; cellular imaging; in vivo; insight; neurotransmitter release; novel therapeutic intervention; public health relevance; voltage

DESCRIPTION (provided by applicant): Detrusor overactivity (DO) is a prevalent medical condition. Despite a growing body of research the pathomechanisms of this condition are still poorly understood and available therapy is ineffective. Calcium (Ca2+) entry through voltage dependent calcium channels (VDCCs) is an important factor for mediating urinary bladder smooth muscle (UBSM) contraction as well as for regulation of neurotransmitter release from nerve terminals. Disruption of this fine balance can result in a voiding dysfunction. This proposal focuses on VDCC CaV2.3 (R-type), its distribution and functional significance in rat urinary bladder and sensory micturition reflex pathways in healthy animals and animals with DO. The overall hypothesis for this grant proposal is that DO-induced neuroplasticity of micturition reflex pathways leads to changes in electrophysiological properties that affect the high voltage activated R-type Ca2+ channel subunit. These changes contribute to an alteration of the micturition reflex through affecting Ca2+ signal patterning in UBSM and bladder sensory neurons. Specific Aim 1: To determine distribution of (1E CaV2.3 (R-type) channel subunit in micturition reflex pathways and characterize changes in their expression associated with DO. Specific Aim 2: To elucidate UBSM and bladder sensory neuron Ca2+ signaling patterns mediated by R-type Ca2+ channels under physiological and pathological conditions. Specific Aim 3: To clarify the physiological significance of the R-type Ca2+ channel subunit in micturition. This proposal takes an integrative approach by applying molecular biology, cell imaging, electrophysiology and in vivo and in vitro functional techniques to identify the CaV2.3 channel in the lower urinary tract (LUT) and define its contribution to Ca2+ signaling under physiological and pathological conditions. To our knowledge, this is the first study addressing the specific role of R-type Ca2+ channel in the LUT. PUBLIC HEALTH RELEVANCE: Results from this study will significantly enhance current knowledge on the specific role of R-type Ca2+ channel in the lower urinary tract, and may provide insight into new therapeutic approaches for the treatment of bladder overactivity.

描述（由申请人提供）： 逼尿肌过度活动 (DO) 是一种常见的疾病。尽管有越来越多的研究，但人们对这种疾病的病理机制仍然知之甚少，现有的治疗方法也无效。钙 (Ca2+) 通过电压依赖性钙通道 (VDCC) 进入是介导膀胱平滑肌 (UBSM) 收缩以及调节神经末梢释放神经递质的重要因素。这种精细平衡的破坏可能导致排尿功能障碍。该提案重点关注 VDCC CaV2.3（R 型）、其在大鼠膀胱中的分布和功能意义以及健康动物和 DO 动物的感觉排尿反射通路。 该拨款提案的总体假设是，DO 诱导的排尿反射通路神经可塑性会导致电生理特性的变化，从而影响高压激活的 R 型 Ca2+ 通道亚基。这些变化通过影响 UBSM 和膀胱感觉神经元中的 Ca2+ 信号模式而导致排尿反射的改变。具体目标 1：确定 (1E CaV2.3（R 型）通道亚基在排尿反射通路中的分布，并表征其与 DO 相关的表达变化。具体目标 2：阐明生理和病理条件下由 R 型 Ca2+ 通道介导的 UBSM 和膀胱感觉神经元 Ca2+ 信号传导模式。具体目标 3：阐明 R 型 Ca2+ 通道的生理意义 排尿亚单位。 该提案采用综合方法，应用分子生物学、细胞成像、电生理学以及体内和体外功能技术来识别下尿路（LUT）中的CaV2.3通道，并确定其在生理和病理条件下对Ca2+信号传导的贡献。据我们所知，这是第一个研究 R 型 Ca2+ 通道在 LUT 中的具体作用的研究。 公共健康相关性：这项研究的结果将显着增强目前对 R 型 Ca2+ 通道在下尿路中具体作用的认识，并可能为治疗膀胱过度活动症的新治疗方法提供见解。