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，特别是压力尿失禁（SUI），在女性退伍军人中很普遍，而且非常令人毛骨悚然。尽管没有生命危险，但SUI大大降低了生活质量，而在女退伍军人中，与抑郁和性侵犯的病史显着相关。 SUI也与阴道分娩密切相关，这可能会受伤 骨盆底的肌肉和器官，包括外部尿道括约肌（EUS）。此外，支配EUS的底座神经在分娩过程中可能会在阿尔科克的运河中受伤，靠近其尿道的神经。因此，在子犬期间造成的伤害代表了独特的神经肌肉损伤：目标肌肉（EUS）及其神经同时受伤。这两次受伤，以及骨盆底的组织和肌肉的伤害与后来的SUI发育密切相关。必须由目标肌肉产生脑衍生的神经营养因子（BDNF），以再生运动神经元并在周围神经损伤后重新染色肌肉。但是，如果肌肉受伤，BDNF会抑制神经肌肉连接（NMJ）修复。因此，当神经及其神经支配的肌肉受伤时，在分娩过程中可能发生的那样，肌肉的BDNF下调会抑制神经再生。我们已经开发了一种新型的模拟分娩损伤的动物模型，并证明神经营养介导的机制可能导致阴道分娩后的延迟且可能不完全的神经变成。电刺激（E-stim）增加了受伤的神经元中的BDNF表达，并促进神经再生。与用BDNF治疗相比，它可能提出一种替代疗法。促进神经再生的E-Stim疗法取得了不同的成功，部分原因是它仅在神经损伤后才被利用，而不是在结合神经和肌肉损伤之后，就像分娩时可能发生的那样。恰恰是因为这是对特定临床相关模型组合神经和肌肉损伤后的E-stim作用机理的研究至关重要的，这对于优化治疗和患者亚群以治疗而至关重要。我们最近有数据表明，模拟分娩损伤后底端神经的E-stim上调了BDNF在Pudendal神经细胞中的BDNF，并促进了尿道的功能恢复。但是，该数据是相关的，而不是因果关系。因此，在该项目中要检验的假设是E-imt提高了恢复 通过BDNF介导的机制模拟分娩损伤。该假设将通过以下特定目标（SO）：SO1进行检验。优化模拟分娩损伤后改善恢复的E-stim范式； SO2。证明具有E-stim的功能的加速恢复与慢性改善相关。 SO3。证明BDNF是必要的，足以足以在模拟分娩损伤后通过补充BDNF加速自发恢复和加速恢复。 SO4。证明E-stim通过BDNF介导的机制有助于从模拟分娩损伤中恢复。该项目将提供关键的临床前数据，以启动临床三角体，以评估E-Stim作为SUI女性退伍军人康复的辅助。分娩后约有1/3的妇女有产后SUI。尽管这在大多数女性中得到了解决，但这些妇女中有几乎一半在5年后重新开发了它，并且在几年后重新开发了一半，这表明产后SUI可以预测后来的SUI。产后SUI的妇女可以构成E-stim临床试验的人群，这可以治疗其目前的动荡和预防SUI的重建。这项研究直接与衰老的康复研发优先区有关。此外，妇女是退伍军人人口中增长最快的部分，占现役军人的14％和20％的新军事新兵，并且是VA研究计划的优先事项。由于女性退伍军人之间的尿失禁和抑郁症如此紧密相关，因此尿失禁症状的改善可能有助于导致抑郁症的恢复。