Neuromuscular junction as a therapeutic target to improve post-traumatic outcomes

神经肌肉接头作为改善创伤后结果的治疗靶点

基本信息

批准号：
10656439
负责人：
Yu-Long Li
金额：
$ 37.61万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656439
关键词：
Accident and Emergency department Acute Address Affect Age Animals Anti-Inflammatory Agents Binding Blood Vessels Cell Line Cessation of life Chronic Clinic Clinical Cyclin-Dependent Kinase 5 Cytokine Receptors Data Dexamethasone Drug Delivery Systems Embryo Emergency Situation Functional disorder Hemorrhage Hindlimb In Vitro Inflammation Inflammatory Interleukin 6 Receptor Interleukin-1 beta Interleukin-6 Ischemia Life Limb structure Link Measurable Mediating Medicine Membrane Modeling Molecular Motor Mus Muscle Muscle Contraction Muscle function Nerve Neuromuscular Junction Neuromuscular Junction Diseases Nicotinic Receptors Operative Surgical Procedures Orthopedics Outcome Patients Pharmaceutical Preparations Polyethylene Glycols Pre-hospital setting Prodrugs Production Prognosis Protein Array Quality of life Recovery Reperfusion Injury Reperfusion Therapy Route Signal Pathway Signal Transduction Site Skeletal Muscle Structure Synapses TNF gene Testing Therapeutic Therapeutic Effect Tissues Tourniquets Trauma Traumatic injury Treatment Efficacy Visit beta catenin cost cytokine design effective therapy emergency service responder improved improved outcome in vivo injured limb injury long term recovery mouse model muscular structure novel novel therapeutics overexpression peripheral membrane protein 43K receptor reinnervation repaired sciatic nerve side effect therapeutic target tool transcriptome sequencing transmission process

项目摘要

Project Summary Severe hemorrhage from extremity injuries is a significant cause of battlefield deaths and preventable trauma fatalities in civilian medicine. Tourniquet use is the most effective means of arresting life-threatening limb hemorrhage in the pre-hospital setting and creating bloodless surgical fields in orthopedic and vascular surgeries; however, tourniquet-related ischemia and subsequent reperfusion (IR) can cause serious IR injuries. These IR injuries have led to the limitations of tourniquet use. Exploring the mechanisms and finding effective therapies can resolve the limitations of tourniquet use and improve outcomes and quality of life in post- traumatic patients. The neuromuscular junction is structured to transmit electrical signals from motor nerve terminals to nicotinic acetylcholine receptors (nAChRs) for affecting muscle function. Our pilot data demonstrated that some nAChR clusters are fragmented in mice with 6 weeks of tourniquet-induced IR. Therefore, in Aim 1, we will determine the relationship between the fragmentation of nAChR clusters and muscle contractile dysfunction in long-term tourniquet-induced IR. Additionally, our preliminary studies have targeted a specific signaling pathway that links fragmentation of nAChR clusters in the injured muscle, namely the inflammatory cytokine-cyclin-dependent kinase 5 (Cdk5-catenin-rapsyn signaling pathway. In Aim 2, we will test if the inflammatory cytokine-Cdk5-catenin-rapsyn signaling pathway mediates fragmentation of nAChR clusters in long-term tourniquet-induced IR. In Aim 3, we will investigate the therapeutic effect of a novel anti- inflammatory drug on long-term functional and structural recovery of the neuromuscular junction via inhibition of pro-inflammatory cytokines in mouse models of tourniquet/IR injury. We will design in vitro and in vivo studies to address our overarching hypothesis that anti-inflammation will promote repair of the neuromuscular junction. Overall, proposed studies will unveil cellular and molecular mechanisms responsible for long-term neuromuscular junction disorder in tourniquet-induced IR. These studies will provide further information that the neuromuscular junction could be a potential therapeutic target in tourniquet/IR injuries, especially through the application of a novel anti-inflammatory drug in this proposal. This approach has significant potential to resolve the limitations of clinical tourniquet use, thereby improving outcomes and quality of life in post- traumatic patients.

项目概要四肢受伤造成的严重出血是战场死亡和可预防创伤的重要原因民用医学领域的死亡人数。使用止血带是阻止危及生命的肢体的最有效方法院前环境中的出血以及在骨科和血管科中创建无血手术野手术；然而，止血带相关的缺血和随后的再灌注 (IR) 可能会导致严重的 IR 损伤。这些红外线损伤导致了止血带使用的限制。探索机制，寻找有效途径治疗可以解决止血带使用的局限性，并改善术后的结果和生活质量。外伤患者。神经肌肉接头的结构是传输来自运动神经的电信号烟碱乙酰胆碱受体 (nAChR) 的末端影响肌肉功能。我们的试点数据研究表明，在 6 周止血带诱导 IR 的小鼠体内，一些 nAChR 簇发生断裂。因此，在目标 1 中，我们将确定 nAChR 簇的碎片与长期止血带引起的 IR 导致肌肉收缩功能障碍。此外，我们的初步研究还靶向连接受伤肌肉中 nAChR 簇片段的特定信号通路，即炎症细胞因子细胞周期蛋白依赖性激酶 5（Cdk5-catenin-rapsyn 信号通路）。在目标 2 中，我们将测试炎症细胞因子-Cdk5-catenin-rapsyn 信号通路是否介导 nAChR 片段化长期止血带引起的 IR 中出现集群。在目标 3 中，我们将研究一种新型抗- 炎症药物通过抑制作用对神经肌肉接头的长期功能和结构恢复止血带/IR损伤小鼠模型中促炎细胞因子的研究。我们将进行体外和体内设计研究旨在解决我们的总体假设，即抗炎将促进神经肌肉的修复交界处。总体而言，拟议的研究将揭示负责长期的细胞和分子机制止血带引起的 IR 中的神经肌肉接头紊乱。这些研究将提供进一步的信息神经肌肉接头可能是止血带/IR损伤的潜在治疗靶点，特别是通过本提案中应用了一种新型抗炎药物。这种方法具有巨大的潜力解决临床止血带使用的局限性，从而改善术后结局和生活质量外伤患者。