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

• 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
• 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

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 肢体创伤的严重出血是战场死亡和可预防创伤的重要原因 平民医药的死亡。止血带的使用是阻止危及生命的肢体最有效的手段 在院前环境中的出血，并在骨科和血管外科中创建无血手术野 然而，止血带相关的缺血和随后的再灌注（IR）可导致严重的IR损伤。 这些IR损伤导致了止血带使用的局限性。探索机制，寻找有效的 治疗可以解决止血带使用的局限性，并改善术后的结局和生活质量。 创伤患者神经肌肉接头的结构是为了传递来自运动神经的电信号 烟碱乙酰胆碱受体（nAChR）的末端，以影响肌肉功能。我们的试点数据 表明，在止血带诱导IR 6周的小鼠中，一些nAChR簇片段化。 因此，在目标1中，我们将确定nAChR簇的片段化与 长期止血带诱导的IR中的肌肉收缩功能障碍。此外，我们的初步研究 靶向一个特定的信号通路，该通路连接受损肌肉中nAChR簇的片段化，即 炎症性细胞周期蛋白依赖性激酶5（Cdk 5-连环蛋白-rapsyn信号通路。在目标2中，我们将 测试炎症性丝氨酸-Cdk 5-连环蛋白-rapsyn信号通路是否介导nAChR片段化 在目标3中，我们将研究一种新的抗- 炎性药物通过抑制神经肌肉接头的长期功能和结构恢复 促炎细胞因子在止血带/IR损伤小鼠模型中的作用。我们将在体外和体内设计 研究，以解决我们的首要假设，抗炎将促进修复的神经肌肉 交界处。总的来说，拟议的研究将揭示长期的细胞和分子机制， 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 一种新型抗炎药在本方案中的应用。这种方法具有很大的潜力， 解决临床止血带使用的局限性，从而改善术后结局和生活质量。 创伤患者