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，以进一步了解 恢复膀胱排空功能的躯体神经再支配机制。 目标1：解决以下问题： ·将生长因子施用到再神经支配的膀胱壁中是否会改善恢复？ ·哪些是最有效的增长因素？将是： a）由分散的膀胱细胞（平滑肌、壁内神经节、间质， 尿路上皮细胞）， B）促进膀胱脊髓运动神经元的新生儿存活的因子;或者， c）最佳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： ·是每侧上的盆神经的一个前膀胱分支，其由膀胱神经的一部分再神经支配。 闭孔神经分支是否足以实现有效的膀胱排空和感觉？ ·切断膀胱分支导致的神经支配丧失是否足以导致膀胱功能丧失 功能或这有足够的保留神经支配通过其他分支，使排尿功能 随着时间的推移而恢复？ ·排尿行为的恢复真的是来自神经转移的新神经通路的结果吗？ 其他的自然恢复吗 ·在去中心化之前进行的闭孔肌至盆神经前分支转移是否会改善 恢复膀胱功能？ 目标3：使用前一个资助周期积累的犬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性质发生了什么变化，这些性质是如何通过改变路线而改变的？ ·什么类型的传出纤维从闭孔神经重新支配膀胱，以及在什么类型的神经上。 这些新的纤维终止于细胞吗？ 新的膀胱传出纤维是来自腹角、交感神经链还是两者？ ·什么类型的传入纤维从闭孔神经生长到膀胱，它们的根是什么？ 器官目标？是尿道炎、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?