Manipulating Macrophage Phenotype in Laryngeal Nerve Repair

控制喉神经修复中的巨噬细胞表型

• 批准号: 8687639
• 负责人: Jonathan Cheetham
• 金额: $ 16.37万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687639
• 关键词: Acute; Address; Adult; Anastomosis - action; Animals; Anterior; Anti-Inflammatory Agents; Anti-inflammatory; Area; Axon; Bilateral; Biological; Biomedical Engineering; Breathing; Canis familiaris; Cell Surface Receptors; Cells; Cervical nerves; Cervical spine; Chest; Chronic; Clinical; Data; Deglutition; Denervation; Distal; Dose; Goals; Healed; Hydrogels; IL4 gene; Immune; Immune response; Immunohistochemistry; Immunology; Injection of therapeutic agent; Injury; Interferons; Interleukin-10; Intervention; Knockout Mice; Label; Laryngeal Nerves; Laryngeal muscle structure; Larynx; Lead; Life; Liquid substance; Macrophage Activation; Modeling; Motor Neurons; Mus; Muscle; Natural regeneration; Neck; Nerve; Operative Surgical Procedures; Paralysed; Patients; Peripheral Nerves; Phenotype; Pneumonia; Population; Process; Rattus; Recovery; Recovery of Function; Recruitment Activity; Recurrent Laryngeal Nerve; Role; Schwann Cells; Site; Structure of phrenic nerve; Surgical sutures; System; Thoracic Surgical Procedures; Thyroid Gland; Time; Tracheostomy procedure; Transgenic Organisms; Translations; Transplantation; Voice; airway obstruction; cell motility; cytokine; functional restoration; healing; immunoregulation; improved; injured; macrophage; nerve injury; novel strategies; peroneal nerve; preclinical study; public health relevance; receptor; regenerative; reinnervation; repaired; research study; response; vocal cord

DESCRIPTION (provided by applicant): Vocal fold paralysis occurs when the recurrent laryngeal nerve (RLN) is injured, most commonly during surgery of the neck or thorax. Immobility of one vocal fold produces a hoarse voice, reduced airflow and aspiration of fluids with swallowing that can lead to pneumonia. Bilateral injury to the RLN can result in potentially life- threatening airway obstruction and the need for tracheostomy. The RLN can regenerate some of its axons, but more than half of patients with paralysis require some form of intervention to correct the airway obstruction and voice changes. This is mostly frequently achieved through reinnervation of the laryngeal muscles to restore function. As spontaneous recovery can occur, current practice is to wait 6-12 months before any intervention is performed. This delay produces chronic changes in the nerve distal to the site of injury and reduces the capacity of axons to regrow and reinnervate the muscles controlling the vocal folds. Our preliminary data definitively demonstrate that the type of macrophages infiltrating the site of nerve repair have a significant impact on healing when reinnervation is delayed. We hypothesize that promotion of an alternately activated or regulatory macrophage phenotype at the site of nerve repair promotes axonal regrowth and functional recovery. In specific aim 1, we will use transgenic knock-out mice to demonstrate the effects of deletion of cell surface receptors that control macrophage phenotype on nerve repair immediately and up to 4 months after injury. We will use mice with deletions for receptors for IFN¿, IL4 and IL10 which, if present, promote classical, alternate or regulatory responses. We will establish the effects of nerve repair immediately and up to 4 months after nerve injury using retrograde labeling. In the second aim, we will use a hydrogel system to deliver high and low dose IL4 and IL10 for a prolonged period to the site of nerve repair in an established model of chronic nerve injury. Nerve repair will be performed at 2 months after injury and axonal regrowth and functional recovery assessed for 4 months after repair. These experiments will improve the understanding of immunomodulation in nerve repair and have their greatest application for RLN injuries or potentially in laryngeal transplantation. T achieve these goals, I have built an exceptional interdisciplinary team who are leading experts in their respective fields to provide support and guidance in clinical translation, immunology, peripheral nerve repair, macrophage phenotype in remodeling and host response. This team will support me in this proposal and through my transition to independence.

描述（由适用提供）：当复发性喉神经（RLN）受伤时，发生声带瘫痪，最常见于颈部或胸部手术。一个声带的固定性会产生嘶哑的声音，减少气流和吞咽吞咽的吸入，可能导致肺炎。双侧损伤RLN可能会导致潜在的威胁性气道异议和气管切开术的需求。 RLN可以再生一些轴突，但是超过一半的麻痹患者需要某种形式的干预措施才能纠正气道目标和声音变化。这是通过重新支配喉肌来恢复功能的最常实现的。由于可能发生赞助恢复，当前的做法是等待6-12个月，然后进行任何干预。这种延迟会导致损伤部位远端神经远处的慢性变化，并降低轴突的能力来完善和加剧控制声褶的肌肉。我们的初步数据明确表明，渗透神经修复部位的巨噬细胞类型对延迟加重时的愈合有重大影响。我们假设促进神经修复部位的替代激活或调节性巨噬细胞表型会促进轴突改革和功能恢复。在特定的目标1中，我们将使用转基因敲除小鼠来证明控制巨噬细胞表型对神经修复的删除的影响，并在受伤后立即和最多4个月。我们将使用带有缺失的小鼠进行IFN¿，IL4和IL10的受体，如果存在，则可以促进经典，替代或调节反应。我们将在神经损伤后使用逆行标签立即建立神经修复的影响，直到4个月。在第二个目标中，我们将使用水凝胶系统在长时间的慢性神经损伤模型中长时间向神经修复部位提供高剂量和低剂量IL4和IL10。神经修复将在受伤和轴突改革后2个月进行，并在修复后4个月评估了功能恢复。这些实验将提高对神经修复中免疫调节的理解，并在RLN损伤或喉移植中具有最大的应用。 T实现这些目标，我建立了一个杰出的跨学科团队，他们是各自领域的领导专家，以提供临床翻译，免疫学，外周神经修复，重塑和宿主反应中的巨噬细胞表型的支持和指导。这个团队将在此提案中支持我，并通过我过渡到独立性。