Developmental plasticity of micturition reflexes

 描述（由申请方提供）：在产前和产后发育期间，尿液储存和定期排泄的相关机制表现出显著变化。虽然成熟的排尿反射在出生后开始发挥作用，但成熟排尿反射的神经通路在出生时就存在，但并不活跃。成人神经系统的损伤或疾病可导致在发育早期突出但在成熟期间受到抑制的原始功能的重新出现。在文献中没有模型来解释这种发展转换。我们已经开发了一种新的模型，在这种竞争性更新应用中进行评估，重点关注排尿反射途径中两类离子通道的可塑性（表达，定位，功能）： 瞬时受体电位通道香草酸家族（TRPV）和Ca 2 +-和/或Ca 2 + -和电压激活的K+通道。我们的总体假设是，感觉肢的可塑性（例如，在出生后早期或脊髓损伤（SCI）后，排尿反射（包括TRPV 4 Ca 2+信号传导和Ca 2 + -（SKCa）和/或Ca 2 + -和电压激活的K通道（BKCa））的成熟（包括排尿神经节、脊髓背根神经节）是成年人排尿反射成熟和原始排尿功能再现的基础。我们提出了一个新的范例，TRPV 4/Ca 2+信号复合物作为一个制动器，成熟的排尿反射在出生后的早期，并根据原始排尿脊髓损伤后在成人中重新出现。目标1：我们假设TRPV 4在出生后早期在尿道和/或膀胱感觉神经元中与SKCa和/或BKCa共表达。在出生后成熟期间，尿道和/或膀胱感觉神经元中TRPV 4/Ca 2+信号传导复合物的可塑性（组织/细胞分布，密度）决定了扩张诱导的排尿反射的促抑制（制动）或促兴奋状态。TRPV 4/Ca 2+复合物的组织/细胞分布和密度有利于出生后早期发育期间扩张诱导的排尿反射的促抑制（制动）状态。目标二：我们假设TRPV 4在出生后早期发育过程中通过与尿道和/或膀胱感觉神经元中的SKCa和/或BKCa相互作用而起到对成熟排尿反射的制动作用。TRPV 4/Ca 2+信号传导复合物激发超极化并阻止递质（例如，ATP）释放。目标3：我们假设SCI诱导的可塑性（组织/细胞分布，密度，功能）的TRPV 4/Ca 2+信号复合体中的尿路和/或膀胱感觉神经元的结果在重新出现的前抑制（制动）状态的扩张诱导的排尿反射和重新出现的原始排尿反射（会阴膀胱）。这些研究将促进我们对SCI后排尿反射成熟和本体事件重演的潜在机制的理解，并为潜在的下尿路靶点提供见解，以改善排尿功能。

 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.