Electrical Stimulation Facilitation of Recovery from Childbirth Injury

产品说明： 尿失禁，特别是压力性尿失禁（SUI），是女性退伍军人中常见且非常麻烦的疾病。虽然不危及生命，但SUI大大降低了生活质量，并且在女性退伍军人中与抑郁症和性侵犯史显着相关。SUI也与阴道分娩儿童密切相关，这可能会损害 骨盆底的肌肉和器官，包括尿道外括约肌（EUS）。此外，支配EUS的阴部神经可能在分娩过程中在Alcock管内损伤，接近其尿道的神经支配。因此，在分娩过程中发生的损伤代表了一种独特的神经肌肉损伤：其中靶肌肉（EUS）及其神经支配同时受损。这两种损伤，沿着骨盆底组织和肌肉的损伤与SUI的后期发展密切相关。周围神经损伤后，靶肌肉必须产生脑源性神经营养因子（BDNF）才能再生运动神经元并使肌肉再神经支配。然而，如果肌肉受伤，BDNF抑制神经肌肉接头（NMJ）修复。因此，当神经及其受神经支配的肌肉都受到损伤时，如分娩期间可能发生的那样，肌肉下调BDNF会抑制神经再生。我们已经开发了一种新的模拟分娩损伤的动物模型，并证明神经营养因子介导的机制可能是阴道分娩后延迟和可能不完全的神经再生的原因。电刺激（e-stim）增加受损神经元中BDNF的表达，促进神经再生。它可能是一种比BDNF治疗并发症更少的替代疗法。促进神经再生的E-stim疗法取得了好坏参半的成功，部分原因是它只在神经损伤后使用，而不是在神经和肌肉联合损伤后使用，而这种情况可能发生在分娩时。正因为如此，在一个特定的临床相关模型的组合神经和肌肉损伤后的e-stim的作用机制的调查是至关重要的优化治疗和患者亚群treat. We最近的数据表明，模拟分娩损伤后的阴部神经的e-stim上调BDNF在阴部神经细胞，促进尿道的功能恢复。然而，这些数据是相互关联的，而不是因果关系。因此，在本项目中要检验的假设是e- stim可以改善恢复 通过脑源性神经营养因子介导的机制从模拟分娩损伤中恢复。该假设将通过以下特定目标（SO）进行检验：SO 1。优化e-stim范例以改善模拟分娩损伤后的恢复; SO2。证明使用e-stim加速功能恢复与慢性改善相关; SO 3。证明BDNF对于阴部神经挤压（PNC）后的自发恢复和模拟分娩损伤后补充BDNF的加速恢复是必要和充分的。SO4。证明e-stim通过BDNF介导的机制促进模拟分娩损伤的恢复。该项目将提供关键的临床前数据，以启动临床试验，评估e-stim作为SUI女性退伍军人康复辅助手段的作用。大约1/3的妇女在分娩后有产后SUI。虽然这在大多数妇女中得到解决，但这些妇女中几乎有一半在5年后重新发展，超过一半在几年后重新发展，表明产后SUI可预测以后的SUI。患有产后SUI的妇女可以构成e-stim临床试验的人群，该试验可以治疗她们目前的尿失禁并预防SUI的再发展。这项研究直接关系到老龄化的康复研发优先领域。此外，女性是退伍军人人口中增长最快的部分，占现役部队的14%和新兵的20%，并且是VA研究计划的优先事项。由于尿失禁和抑郁症在女性退伍军人中密切相关，改善尿失禁症状可能有助于从抑郁症中恢复。

DESCRIPTION: Urinary incontinence, particularly stress urinary incontinence (SUI), is common and very bothersome among female veterans. Although not life threatening, SUI greatly reduces quality of life and, among female veterans is significantly correlated with a history of depression and sexual assault. SUI is also strongly correlated with vaginal delivery of children, which can injure the muscles, and organs of the pelvic floor, including the external urethral sphincter (EUS). In addition, the pudendal nerve, which innervates the EUS, can be injured in Alcock's canal during delivery, proximal to its innervations of the urethra. Thus, the injuries incurred during childbirt represent a unique neuromuscular injury: one in which both the target muscle (the EUS) and its innervation are injured simultaneously. These two injuries, along with injuries to the tissues and muscles of the pelvic floor are strongly correlated with later development of SUI. Brain-derived neurotrophic factor (BDNF) must be produced by the target muscle to regenerate motoneurons and reinnervate the muscle after peripheral nerve injury. However, if muscle is injured, BDNF inhibits neuromuscular junction (NMJ) repair. Therefore, when both a nerve and its innervated muscle are injured, as can occur during childbirth, BDNF downregulation by the muscle inhibits nerve regeneration. We have developed a novel animal model of simulated childbirth injury and have demonstrated that a neurotrophin- mediated mechanism could be responsible for delayed and possibly incomplete neuroregeneration after vaginal delivery. Electrical stimulation (e-stim) increases BDNF expression in injured neurons and promotes nerve regeneration. It may present an alternative therapy with fewer complications than treatment with BDNF. E-stim therapy to promote nerve regeneration has had mixed success, in part because it has only been utilized after nerve injury, not after a combination nerve and muscle injury, as can occur in childbirth. Precisely because of this, investigation of the mechanism of action of e-stim after a combinatorial nerve and muscle injury in a specific clinically related model is crucial for optimizing the therapy and the patient subpopulation to treat. We have recent data that e-stim of the pudendal nerve after simulated childbirth injury upregulates BDNF in pudendal nerve cells and promotes functional recovery of the urethra. However, this data is correlative rather than causative. Therefore, the hypothesis to be tested in this project is that e- stim improves recovery from simulated childbirth injury via a BDNF-mediated mechanism. This hypothesis will be tested via the following specific objectives (SO): SO1. Optimize an e-stim paradigm for improvement of recovery after simulated childbirth injury; SO2. Demonstrate that accelerated recovery of function with e- stim correlates with chronic improvement; SO3. Demonstrate that BDNF is necessary and sufficient for spontaneous recovery after pudendal nerve crush (PNC) and accelerated recovery with supplemental BDNF after simulated childbirth injury. SO4. Demonstrate that e-stim facilitates recovery from simulated childbirth injury via a BDNF-mediated mechanism. This project will provide critical pre-clinical data to initiate a clinical tril to assess e-stim as an adjuvant to rehabilitation for female veterans with SUI. Approximately 1/3 of women have postpartum SUI following delivery. Although this resolves in most women, almost half of these women redevelop it 5 years later and over half redevelop it years later, indicating that postpartum SUI is predictive of later SUI. Women with postpartum SUI could constitute the population for a clinical trial of e- stim, which could treat their current incontinence and preven redevelopment of SUI. This research directly relates to the Rehabilitation R&D Priority Area of Aging. In addition, women are the fastest growing segment of the veteran population, representing 14% of active duty forces and 20% of new military recruits, and are a priority for the VA research program. Since incontinence and depression are so closely correlated among female veterans, improvement of incontinence symptoms may help lead to recovery from depression.