Developmental plasticity of micturation reflexes

描述(申请人提供)：有一些儿童排尿功能障碍，可能是由于出生后排尿反射的异常成熟所致。最近的研究表明，儿童下尿路(LUT)功能障碍与成人膀胱过度活动有很强的相关性。因此，了解在出生后时期调节排尿功能的神经控制的因素可能有助于深入了解儿童和成人的排尿功能障碍。此外，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就很突出，但在神经成熟时被抑制。因此，对排尿反射通路的发育研究可能对成人膀胱功能神经源性障碍的机制提供关键的见解。这一建议的中心假设是，中枢神经系统(CNS)和外周神经系统(PNS)的变化都会促使排尿反射成熟。发生在出生后早期的排尿功能的神经控制的显著变化可能是由多种因素介导的，包括成熟的脊髓上机制(促肾上腺皮质激素释放因子、CRF/CRF受体系统)的上调以及神经元和靶器官(节后神经节后神经和膀胱)相互作用的改变。在这一竞争性更新应用中，我们提出的AIMS将使用多学科实验方法，包括大鼠模型和新的慢性过表达神经生长因子(NGF)小鼠系(UPII-NGFv2)，为发育诱导的排尿反射神经控制变化提供进一步的机制洞察。该建议的目的是：(1)鉴定腰骶段脊髓中的CRF/CRF受体系统，并确定CRF/CRF受体系统在LUT通路中的功能作为发育的函数；(2)确定UPII-NGFv2小鼠成熟排尿功能加速发展的机制；(3)确定主要骨盆神经节(MPG)中膀胱节后细胞在发育过程中的功能特性，导致成人电生理特性多样化的潜在通道特性，以及膀胱NGF对这些特性的贡献。 公共卫生相关性：项目叙述 有许多儿童排尿功能障碍，可能是由于排尿反射在出生后异常成熟所致。最近的研究表明，儿童下尿路功能障碍与成人膀胱过度活动有很强的相关性。因此，了解在出生后时期调节排尿功能的神经控制的因素可能有助于深入了解儿童和成人的排尿功能障碍。此外，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就很突出，但在神经成熟时被抑制。因此，对排尿反射通路的发育研究可能对成人膀胱功能神经源性障碍的机制提供关键的见解。这些研究将集中在脊髓下行通路中重要的神经递质/受体系统的发展以及神经元与靶器官(即节后神经节后神经和膀胱)相互作用的变化和机制，这些变化和机制奠定了排尿功能成熟的基础。预计这些研究将为儿童和成人排尿功能障碍的潜在靶点和治疗干预提供见解。

DESCRIPTION (provided by applicant): There are a number of childhood voiding dysfunctions that may be attributable to abnormal postnatal maturation of voiding reflexes. Recent studies have shown a strong correlation between childhood lower urinary tract (LUT) dysfunction and adult overactive bladder. Thus, understanding the factors that regulate the neural control of voiding function during the postnatal period may provide insight into childhood and adult voiding dysfunction. Furthermore, injuries or diseases of the adult nervous system can lead to the reemergence of primitive functions that were prominent early in development but then were suppressed during neural maturation. Therefore, developmental studies of micturition reflex pathways are likely to provide key insights into the mechanisms underlying neurogenic disorders of urinary bladder function in adults. The central hypothesis of this proposal is that changes in both the central nervous system (CNS) and peripheral nervous system (PNS) drive micturition reflex maturation. Marked changes in the neural control of voiding function that occur during early postnatal development may be mediated by multiple factors, including upregulation of mature supraspinal mechanisms (corticotropin releasing factor, CRF/CRF receptor system) and changes in neuron and target organ (postganglionic neuronyenurinary bladder) interactions. In this competitive renewal application, we propose aims that will provide further mechanistic insight into developmental-induced changes in the neural control of micturition reflexes using a multidisciplinary experimental approach involving a rat model as well as a novel, chronic overexpressing nerve growth factor (NGF) mouse line (UPII-NGFv2). The aims of this proposal are: (1) to characterize the CRF/CRF receptor system in the lumbosacral spinal cord and to define the function of the CRF/CRF receptor system in LUT pathways as a function of development; (2) to determine the mechanisms underlying an accelerated development of mature voiding function in UPII-NGFv2 mice; (3) to define the functional properties of bladder postganglionic cells in the major pelvic ganglion (MPG) during development, the underlying channel properties that contribute to the diversity of electrophysiological properties in the adult and the contribution of urinary bladder NGF to these properties. PUBLIC HEALTH RELEVANCE: Project Narrative There are a number of childhood voiding dysfunctions that may be attributable to abnormal postnatal maturation of voiding reflexes. Recent studies have shown a strong correlation between childhood lower urinary tract dysfunction and adult overactive bladder. Thus, understanding the factors that regulate the neural control of voiding function during the postnatal period may provide insight into childhood and adult voiding dysfunction. Furthermore, injuries or diseases of the adult nervous system can lead to the reemergence of primitive functions that were prominent early in development but then were suppressed during neural maturation. Therefore, developmental studies of micturition reflex pathways are likely to provide key insights into the mechanisms underlying neurogenic disorders of urinary bladder function in adults. These studies will focus on the development of the prominent neurotransmitter/receptor system in descending spinal pathways and changes and mechanisms involved in neuron and target organ (i.e., postganglionic neuronyenurinary bladder) interactions that underlie maturation of voiding function. It is anticipated that these studies will provide insights into potential targets and therapeutic interventions for childhood and adult voiding dysfunctions.