Investigating Injury Tolerance and Mechanisms of Neonatal Brachial Plexus Palsy and Associated Injuries

研究新生儿臂丛神经麻痹及相关损伤的损伤耐受性和机制

• 批准号: 10366901
• 负责人: Sriram Balasubramanian
• 金额: $ 48.64万
• 依托单位: WIDENER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366901
• 关键词: 3-Dimensional; Accounting; Acute; Animals; Area; Biochemical; Biological Assay; Biological Markers; Biomechanics; Brachial plexus structure; Cadaver; Cerebrospinal Fluid; Childbirth; Clinical; Complex; Complication; Computer Models; Data; Development; Devices; Diagnosis; Diagnostic; Discipline of obstetrics; Early Diagnosis; Early Intervention; Early treatment; Electrophysiology (science); Elements; Event; Failure; Fetus; Functional disorder; Gamma Motor Neurons; Goals; Head and neck structure; Hemorrhage; Histologic; Human; In Situ; Inflammatory Response; Injury; Intervention; Knowledge; Lateral; Lead; Maps; Modeling; Molecular; Morphology; Motor Neurons; Neonatal; Neurons; Outcome; Paralysed; Pathologic; Pathology; Pelvis; Prevention; Prevention strategy; Property; Proteomics; Publishing; Reporting; Research; Research Priority; Risk; Risk Factors; Science; Serum; Spinal; Spinal Cord; Spinal cord injury; Stretching; Testing; Therapeutic; Tissues; Training; United States National Institutes of Health; Visualization software; Work; avulsion injury; base; biochemical model; clinical development; clinical diagnostics; clinically relevant; combinatorial; diagnostic tool; disability; early detection biomarkers; fetal; force sensor; functional loss; functional status; in silico; in vivo; injury prevention; innovation; insight; long-term sequelae; molecular marker; motor neuron degeneration; neonatal care; neuroinflammation; next generation; novel; porcine model; predictive modeling; predictive tools; pressure; prevent; primipara; response; severe injury; simulation; tool; treatment strategy

Neonatal Brachial Plexus Palsy (NBPP) is a complication of childbirth that can result in significant long-term sequelae. NBPP associated injuries often include cases of spinal cord injury (SCI) and are very poorly understood. Our long-term research goals are to develop both prevention and treatment strategies for NBPP. Consequently, objectives of this study are to use our novel and unique clinically-relevant neonatal piglet model: a) To identify brachial plexus (BP) strains and forces that lead to morphological and functional SCI by investigating the effects of BP stretch on acute pathology and functionality within the spinal cord (SC), b) To investigate clinically-relevant systemic biomarkers for early diagnosis of SCI during NBPP, and c) To develop computational models of maternal pelvis and fetus that predict risk of NBPP and associated SCI during complicated NBPP delivery scenarios. Based on our preliminary work, our central hypothesis is that moderate to severe BP stretches will transmit forces to SC resulting in SC tissue damage, which are also observable as high expression of systemic injury biomarkers in the serum and cerebrospinal fluid, and suppression or loss of motor neuron excitability. Our innovative approach is aimed at developing new knowledge of acute NBPP injury mechanisms and report SCI tolerance values of BP strains and forces. These data will enable novel clinical tools for diagnosis and prevention, as well as suggest targets for early clinical interventions for NBPP. We will test the overall hypothesis through the following independent specific aims: 1) To determine whether moderate to severe BP stretches will lead to SCI as evident by acute SCI markers in situ, functional loss in motor neurons and systemic acute SCI biomarkers, and 2) To identify delivery maneuvers and NBPP risk factors that lead to abnormal BP strains and forces, increasing the likelihood of associated SCI. The expected outcomes of this work are the first ever data on: 1) morphological and functional injury outcomes that help determine SCI tolerance values of BP strains and forces during BP stretch, 2) molecular biomarkers that can enable early diagnosis of SCI, and 3) developing highly biofidelic computational models for NBPP prediction and obstetric training. The results will also have an important positive impact, because, they lay the groundwork to develop a new class of targeted clinical interventions.

新生儿臂丛神经麻痹 (NBPP) 是一种分娩并发症，可导致严重的长期影响 后遗症。 NBPP 相关损伤通常包括脊髓损伤 (SCI) 病例，并且病情非常严重 明白了。我们的长期研究目标是制定 NBPP 的预防和治疗策略。 因此，本研究的目标是使用我们新颖且独特的临床相关新生仔猪模型： a) 通过以下方式识别导致形态和功能性 SCI 的臂丛神经 (BP) 应变和力： 研究血压拉伸对脊髓 (SC) 内急性病理和功能的影响，b) 研究用于 NBPP 期间早期诊断 SCI 的临床相关全身生物标志物，以及 c) 开发 预测 NBPP 和相关 SCI 风险的母体骨盆和胎儿计算模型 复杂的 NBPP 交付场景。根据我们的初步工作，我们的中心假设是适度的 严重的血压拉伸会将力传递到 SC，导致 SC 组织损伤，这也可以观察到 血清和脑脊液中全身损伤生物标志物的高表达，以及抑制或丧失 运动神经元的兴奋性。我们的创新方法旨在开发急性 NBPP 损伤的新知识 机制并报告 BP 应变和力的 SCI 耐受值。这些数据将使新的临床工具成为可能 诊断和预防，并提出 NBPP 早期临床干预的目标。我们将测试 通过以下独立的具体目标得出总体假设： 1）确定是否中等至 严重的血压扩张将导致 SCI，如原位急性 SCI 标记、运动功能丧失 神经元和全身急性 SCI 生物标志物，以及 2) 识别递送操作和 NBPP 风险 导致异常血压应变和力量的因素，增加了相关 SCI 的可能性。这 这项工作的预期结果是有史以来第一个关于以下方面的数据：1）形态和功能损伤结果 帮助确定血压拉伸期间血压应变和力的 SCI 耐受值，2) 分子生物标志物 可以实现 SCI 的早期诊断，并且 3) 开发用于 NBPP 预测的高度生物逼真的计算模型 和产科培训。结果也将产生重要的积极影响，因为，它们奠定了基础 开发一类新的有针对性的临床干预措施。