Developmental plasticity of micturition reflexes

 描述(由申请人提供)：尿液储存和定期排出的机制在出生前和出生后的发育过程中表现出显著的变化。虽然成熟的排尿反射在出生后就开始发挥作用，但成熟的排尿反射背后的神经通路在出生时就已经存在，但并不活跃。成人神经系统的损伤或疾病可能会导致原始功能的重新出现，这些功能在发育早期是突出的，但在成熟时被抑制。文献中没有模型来解释这种发育转变。我们开发了一个新的模型，在这个竞争性更新应用中进行评估，重点是两类离子通道在排尿反射通路中的可塑性(表达、定位、功能)： 瞬时受体电位通道香草素家族(TRPV)和钙离子和/或钙离子和电压激活的K+通道。我们的总体假设是，在出生后早期或脊髓损伤(SCI)后，感觉肢(如尿路上皮、背根神经节)的排尿反射的可塑性涉及TRPV4钙信号和/或钙离子(SKCa)和/或钙和电压激活的钾通道(BKCa)，是成人排尿反射成熟和原始排尿功能恢复的基础。我们提出了一种新的范式，即TRPV4/钙信号复合体在出生后早期对成熟的排尿反射起到刹车作用，并为成年脊髓损伤后原始排尿的重新出现奠定了基础。目的1：我们假设TRPV4在出生后早期与SKCa和/或BKCa在尿路上皮和/或膀胱感觉神经元中共表达。在出生后成熟的过程中，尿路上皮和/或膀胱感觉神经元中TRPV4/钙信号复合体的可塑性(组织/细胞分布、密度)决定了扩张诱导的排尿反射的前抑制(制动)或前兴奋状态。TRPV4/Ca~(2+)复合体的组织/细胞分布和密度有利于在出生后发育早期扩张诱导的排尿反射的前抑制(制动)状态。目的2：我们假设TRPV4通过与尿路上皮和/或膀胱感觉神经元中的SKCa和/或BKCa相互作用，在出生后早期对成熟的排尿反射起到刹车作用。TRPV4/Ca~(2+)信号复合体引起超极化，阻止递质(如ATP)的释放。目的：我们假设脊髓损伤后尿路上皮和/或膀胱感觉神经元中TRPV4/钙信号复合体的可塑性(组织/细胞分布、密度、功能)导致扩张诱导的排尿反射的前抑制(制动)状态和原始排尿反射(会阴-膀胱)的重新出现。这些研究将促进我们对脊髓损伤后排尿、反射成熟和本体事件重现的机制的理解，并为改善排尿功能的潜在下尿路靶点提供见解。

 DESCRIPTION (provided by applicant): The mechanisms involved in the storage and periodic elimination of urine exhibit marked changes during prenatal and postnatal development. Although the mature micturition reflex becomes functional during the postnatal period, the neural pathways underlying the mature voiding reflex are present at birth but are not active. Injuries or diseases of the adult nervous system can lead to the reemergence of primitive functions that were prominent early in development but suppressed during maturation. There is no model in the literature to explain this developmental switch. We have developed a novel model to be evaluated in this competitive renewal application that focuses on the plasticity (expression, localization, function) of two classes of ion channels in micturition reflex pathways: the transient receptor potential channel vanilloid family (TRPV) and Ca2+- and/or Ca2+ - and voltage-activated K+ channels. Our overall hypothesis is that plasticity in the sensory limb (e.g., urothelium, dorsal root ganglia) of the micturition reflex during the early postnatal period or following spinal cord injury (SCI) involving TRPV4 Ca2+ signaling and Ca2+ - (SKCa) and/or Ca2+ - and voltage-activated K channels (BKCa) underlies micturition reflex maturation and reemergence of primitive voiding function in the adult. We propose a novel paradigm whereby the TRPV4/Ca2+signaling complex acts as a brake to the mature micturition reflex during the early postnatal period and underlies reemergence of primitive voiding following SCI in the adult. Aim 1: We hypothesize that TRPV4 is co- expressed in urothelium and/or bladder sensory neurons with SKCa and/or BKCa during the early postnatal period. Plasticity (tissue/cell distribution, density) in the TRPV4/Ca2+ signaling complex in the urothelium and/or bladder sensory neurons during postnatal maturation determines the pro-inhibitory (brake) or pro- excitatory state of the distention-induced voiding reflex. The tissue/cellular distribution an density of the TRPV4/Ca2+ complex favors the pro-inhibitory (brake) state of the distention-induced voiding reflex during early postnatal development. Aim 2: We hypothesize that TRPV4 functions as a brake to the mature voiding reflex during early postnatal development through interactions with SKCa and/or BKCa in urothelium and/or bladder sensory neurons. The TRPV4/Ca2+ signaling complex elicits hyperpolarization and prevents transmitter (e.g., ATP) release. Aim 3: We hypothesize that SCI-induced plasticity (tissue/cell distribution, density, function) in the TRPV4/Ca2+signaling complex in the urothelium and/or bladder sensory neurons results in the reemergence of the pro-inhibitory (brake) state of the distention-induced voiding reflex and reemergence of primitive voiding reflexes (perineal-to-bladder). These studies will advance our understanding of mechanisms underlying micturition reflex maturation and recapitulation of ontological events following SCI and provide insights into potential lower urinary tract targets to improve voiding function.