Electrical Stimulation Facilitation of Recovery from Childbirth Injury

电刺激促进产伤恢复

• 批准号: 8679664
• 负责人: MARGOT S. DAMASER
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679664
• 关键词: Adjuvant; Adverse event; Aging; Alternative Therapies; Anatomy; Animal Model; Area; Binding; Biochemical; Brain-Derived Neurotrophic Factor; Child; Childbirth; Chronic; Clinical; Clinical Data; Clinical Trials; Data; Development; Down-Regulation; Electric Stimulation; Electromyography; Female; Frequencies; Future; Histology; Incontinence; Injury; Investigation; Lead; Life; Mediating; Mental Depression; Methods; Military Personnel; Modeling; Motor Neurons; Muscle; Natural regeneration; Nerve; Nerve Crush; Nerve Regeneration; Neuromuscular Junction; Neurons; Organ; Outcome; Patients; Pelvic Floor Muscle; Pelvic floor structure; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Population; Postpartum Period; Quality of life; Recording of previous events; Recovery; Recovery of Function; Recruitment Activity; Rehabilitation therapy; Research; Schwann Cells; Simulate; Skeletal Muscle; Sphincter; Stress Urinary Incontinence; Striated Muscles; Symptoms; Testing; Time; Tissues; Urethra; Urethral sphincter; Urinary Incontinence; Vagina; Vaginal delivery procedure; Veterans; Woman; Work; combinatorial; density; functional outcomes; improved; injured; myelination; nerve injury; nerve supply; neuromuscular; neurotrophic factor; novel; pre-clinical; pressure; prevent; programs; public health relevance; receptor; reinnervation; repaired; research and development; sexual assault; success

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.

描述： 尿失禁，特别是压力性尿失禁（SUI），在女性退伍军人中很常见并且非常令人烦恼。尽管不会危及生命，但 SUI 极大地降低了生活质量，并且在女性退伍军人中，SUI 与抑郁症和性侵犯史显着相关。 SUI 还与儿童的阴道分娩密切相关，这可能会伤害 盆底的肌肉和器官，包括尿道外括约肌 (EUS)。此外，支配 EUS 的阴部神经在分娩过程中可能会在靠近尿道神经支配的阿尔科克管中受伤。因此，分娩过程中发生的损伤代表了一种独特的神经肌肉损伤：目标肌肉（EUS）及其神经支配同时受伤。这两种损伤以及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，目标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重新支配肌肉。然而，如果肌肉受伤，BDNF 会抑制神经肌肉接头 (NMJ) 修复。因此，当神经及其受神经支配的肌肉都受伤时（如分娩过程中可能发生的情况），肌肉下调 BDNF 会抑制神经再生。我们开发了一种模拟分娩损伤的新型动物模型，并证明神经营养蛋白介导的机制可能导致阴道分娩后延迟且可能不完全的神经再生。电刺激 (e-stim) 会增加受损神经元中 BDNF 的表达并促进神经再生。它可能是一种比 BDNF 治疗并发症更少的替代疗法。促进神经再生的电子刺激疗法取得了不同程度的成功，部分原因是它仅在神经损伤后使用，而不是在分娩时发生的神经和肌肉联合损伤后使用。正因为如此，在特定的临床相关模型中研究组合神经和肌肉损伤后 e-stim 的作用机制对于优化治疗和要治疗的患者亚群至关重要。我们最近的数据表明，模拟分娩损伤后对阴部神经进行电刺激可上调阴部神经细胞中的 BDNF，促进尿道功能恢复。然而，这些数据是相关的，而不是因果关系。因此，本项目要测试的假设是 e-stim 改善恢复 通过 BDNF 介导的机制模拟分娩损伤。该假设将通过以下具体目标 (SO) 进行检验：SO1。优化电子刺激范例，以改善模拟分娩损伤后的恢复；二氧化硫。证明通过 e-stim 加速功能恢复与慢性改善相关；三氧化硫。证明 BDNF 对于阴部神经挤压 (PNC) 后的自然恢复是必要且充分的，并且在模拟分娩损伤后补充 BDNF 可以加速恢复。 SO4。证明电子刺激通过 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，以启动一项临床试验，以评估 e-stim 作为 SUI 女性退伍军人康复辅助剂的作用。大约 1/3 的女性在分娩后会出现产后 SUI。尽管这种情况在大多数女性中都会得到解决，但几乎一半的女性会在 5 年后再次出现这种情况，超过一半的女性会在几年后再次出现这种情况，这表明产后 SUI 是以后 SUI 的先兆。患有产后 SUI 的女性可以构成 estim 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 再次发生。这项研究与老龄化康复研发优先领域直接相关。此外，女性是退伍军人中增长最快的群体，占现役军人的 14% 和新兵的 20%，并且是退伍军人管理局研究项目的重点。由于尿失禁和抑郁症在女性退伍军人中密切相关，因此尿失禁症状的改善可能有助于抑郁症的康复。