Repair of Bladder Function after Cauda Equina Injury

描述（由申请人提供）：脊髓圆锥综合征由脊髓骶部和相关腰骶根的创伤引起。这种伤害会导致下肢瘫痪和感觉障碍、疼痛，以及膀胱、肠道和性功能障碍。目前对于这些损伤的患者还没有成功的治疗方法。我们建立了一个临床相关的大鼠脊髓圆锥/马尾损伤及修复模型。在这个模型中，腰骶腹侧神经根从脊髓表面撕脱，随后手术植入髓圆锥。在最初的研究阶段，我们证明了这种腹侧根植入策略具有神经保护作用，促进轴突再生，并导致下尿路的功能性神经再生。该项目的更新有三个新的目的：1)确定腰骶腹侧根撕脱伤（VRA）损伤后自主神经元和运动神经元的细胞死亡机制；2)确定米诺环素和补体抑制的潜在神经保护作用；3)确定二甲胺四环素和/或补体抑制是否可以增强腰骶椎弓根损伤后急性和延迟手术植入髓圆锥后下尿路的功能性再神经支配。我们将采用联合治疗策略研究腰骶部VRA损伤和修复后下尿路的神经元死亡机制、神经保护和功能性再神经支配。我们将进行手术根撕脱术和植入术、药物治疗、免疫组织化学、电子显微镜、逆行示踪技术、体视学和下尿路功能尿动力学研究。我们提出的研究将更好地了解马尾近端损伤后脊髓自主神经和运动神经元死亡的机制。我们还将研究新的药理学策略，以保护这些神经元免受运动根损伤诱导的细胞死亡，并结合根植入来增强下尿路的功能。我们相信，我们的建议具有转化研究潜力，为髓圆锥/马尾损伤患者开发新的治疗方法。

DESCRIPTION (provided by applicant): A conus medullaris syndrome results from trauma to the sacral portion of the spinal cord and associated lumbosacral roots. Such injuries cause paralysis and sensory impairment of the lower extremities, pain, as well as bladder, bowel, and sexual dysfunctions. No successful treatments are presently available for patients with these injuries. We have developed a clinically relevant model for the study of conus medullaris/ cauda equina injury and repair in the rat. In this model, lumbosacral ventral roots are avulsed from the surface of the spinal cord and subsequently surgically implanted into the conus medullaris. During the initial research period, we demonstrated that this ventral root implantation strategy is neuroprotective, promotes axonal regeneration, and results in functional reinnervation of the lower urinary tract. The renewal of this project has three new aims: 1) to determine cell death mechanisms of autonomic and motor neurons after a lumbosacral ventral root avulsion (VRA) injury; 2) to determine potential neuroprotective effects of minocycline and complement inhibition; 3) determine whether minocycline and/or complement inhibition may augment functional reinnervation of the lower urinary tract after a lumbosacral VRA injury followed by acute and delayed surgical implantations of avulsed roots into the conus medullaris. We will use a combined therapeutic strategy approach to study neuronal death mechanisms, neuroprotection, and functional reinnervation of the lower urinary tract after lumbosacral VRA injury and repair. We will perform surgical root avulsions and implantations, pharmacological treatment, immunohistochemistry, electron microscopy, retrograde tracing techniques, stereology, and functional urodynamic studies of the lower urinary tract. Our proposed studies will provide a better understanding of death mechanisms for autonomic and motor neuron death in the spinal cord after proximal cauda equina injuries. We will also investigate new pharmacological strategies to protect these neurons against motor root injury-induced cell death in combination with root implantation to augment the function of the lower urinary tract. We believe that our proposal has translational research potential for the development of new treatments for patients with conus medullaris/cauda equina injuries.