Bladder, Urethra and Anal Sphincter Reinnervation

摘要： 本次更新申请中的动物研究将与临床试验研究平行进行，以进一步了解 躯体神经再支配恢复膀胱排空功能的机制。 目标1：解决以下问题： ·将生长因子注入重新支配的膀胱壁是否会促进恢复？ ·哪些是最有效的增长因素？它会是： A)分散的膀胱细胞(平滑肌、壁间神经节、间质、 尿路上皮细胞)， B)促进新生膀胱脊髓运动神经元存活的因素；或 C)最佳地吸引来自供体闭孔神经的躯体运动纤维的因素？ ·哪些生长因子促进功能最佳的传入神经再支配？ 目标2：解决以下问题： ·盆腔神经的前膀胱支是两侧的一个分支，由骨盆神经的一部分支配 闭孔神经支是否足以实现有效的膀胱排空和感觉？ ·仅切断膀胱分支造成的神经缺失就足以导致膀胱缺失吗 功能或这充分保留了通过其他分支的神经支配，从而排尿功能 会随着时间恢复吗？ ·排尿行为的恢复真的是神经转移的新神经通路的结果还是 其他一些自发的康复吗？ ·去中心化前进行盆腔神经前支移位术后，会有改善吗？ 膀胱功能恢复了吗？ 目标3：使用前几个筹资周期积累的犬类组织库回答以下问题 以及这些拟议研究中的新动物： ·切断轴突的运动神经的哪些特性发生了变化，这些特性是如何通过改道而改变的？ ·什么类型的传出纤维从闭孔神经重新支配膀胱，以及在什么类型的 细胞这些新纤维会终止吗？ ·新的膀胱传出纤维来自腹角、交感神经节还是两者兼而有之？ ·哪些类型的传入纤维从闭孔神经生长到膀胱中，它们的内径是什么？ 器官靶标？是尿路上皮、壁内神经节、肌肉还是血管？

Abstract: The animal studies in this renewal application will parallel the clinical trial studies to further understand the mechanisms of somatic reinnervation for restoration of bladder emptying function. Aim 1: Address the following questions: • Will administration of growth factors into the reinnervated urinary bladder wall improve recovery? • Which are the most effective growth factors to use? Will it be: a) Factors produced by the decentralized bladder cells (smooth muscle, intramural ganglia, interstitial, urothelial cells), b) Factors that promote neonatal survival of bladder spinal motoneurons; or, c) Factors that optimally attract the somatic motor fibers from the donor obturator nerve? • What growth factors promote functionally optimal afferent reinnervation? Aim 2: Address the following questions: • Is the one anterior vesical branch of the pelvic nerve on each side that is reinnervated by a portion of the obturator nerve branch sufficient to achieve effective bladder emptying and sensation? • Is the loss of innervation from transecting vesical branches alone enough to result in loss of bladder function or this there sufficiently retained innervation through other branches such that the voiding function recovers with time? • Is the recovery of voiding behavior truly the result of the new neural pathway from the nerve transfer or some other spontaneous recovery? • Will obturator to anterior branch of the pelvic nerve transfer performed before decentralization improve recovery of bladder function? Aim 3: Answer the following questions using the canine tissue bank accrued from the previous funding cycles and from the new animals in these proposed studies: • What properties have changed in the axotomized motor nerves and how are these altered by rerouting? • What types of efferent fibers are reinnervating the bladder from the obturator nerve and on what type of cells do these new fibers terminate? • Do the new bladder efferent fibers originate from the ventral horn, sympathetic chain ganglia or both? • What types of afferent fibers are growing into the bladder from the obturator nerve and what are their en- organ targets? Is it urothelium, intramural ganglia, muscles, or blood vessels?