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：
10420384
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/10420384
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 Time Tissues Tourniquets Trauma Traumatic injury Treatment Efficacy Visit base beta catenin cost cytokine design effective therapy emergency service responder improved improved outcome in vivo injured limb injury mouse model muscular structure novel novel therapeutics overexpression peripheral membrane protein 43K receptor reinnervation repaired sciatic nerve side effect therapeutic target tool transcriptome sequencing

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 Time Tissues Tourniquets Trauma Traumatic injury Treatment Efficacy Visit base beta catenin cost cytokine design effective therapy emergency service responder improved improved outcome in vivo injured limb injury mouse model muscular structure novel novel therapeutics overexpression peripheral membrane protein 43K receptor reinnervation repaired sciatic nerve side effect therapeutic target tool transcriptome sequencing

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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.

项目摘要肢体伤害的严重出血是战场死亡和可预防的创伤的重要原因平民死亡。止血带的使用是逮捕威胁生命的肢体的最有效手段在院前环境中出血，并在骨科和血管中形成无血外科手术场手术；但是，止血带相关的缺血和随后的再灌注（IR）可能造成严重的IR受伤。这些IR损伤导致了止血带使用的局限性。探索机制并发现有效疗法可以解决止血带使用的局限性，并改善后的结局和生活质量创伤性患者。神经肌肉连接的结构是从运动神经传输电信号的烟碱乙酰胆碱受体（NACHRS）的末端用于影响肌肉功能。我们的飞行员数据证明某些NACHR簇在小鼠中被散布，并具有6周的止血带引起的IR。因此，在AIM 1中，我们将确定NACHR簇的分裂与长期止血带引起的IR中的肌肉收缩功能障碍。此外，我们的初步研究针对特定的信号通路，该途径连接了受伤肌肉中NACHR簇的碎片，即炎性细胞因子 - 环胞周期蛋白依赖性激酶5（CDK5-Catenin-rapsyn信号通路。在AIM 2中，我们将测试炎症性细胞因子-CDK5-catenin-rapsyn信号通路是否介导了NACHR的碎片长期止血带引起的IR中的集群。在AIM 3中，我们将研究一种新型抗的治疗作用炎症药通过抑制神经肌肉结的长期功能和结构恢复止血带/IR损伤的小鼠模型中的促炎性细胞因子。我们将在体外和体内设计解决我们总体假设的研究，即抗炎将促进神经肌肉的修复交界处。总体而言，拟议的研究将揭示导致长期的细胞和分子机制止血带引起的IR中的神经肌肉连接障碍。这些研究将提供进一步的信息神经肌肉连接处可能是止血带/红外伤害的潜在治疗靶点，尤其是通过在该提案中应用一种新型的抗炎药。这种方法具有很大的潜力解决临床止血带使用的局限性，从而改善后的结果和生活质量创伤性患者。