Ectopic Olfactory Receptor Guided Facial Nerve Regeneration

异位嗅觉受体引导面神经再生

• 批准号: 10575837
• 负责人: Shelly Elese Sakiyama-Elbert
• 金额: $ 45.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575837
• 关键词: Ablation; Address; Adult; Allografting; Anastomosis - action; Antibodies; Autologous Transplantation; Axon; Axotomy; Blinking; Bundling; Cell Survival; Cells; Chemotaxis; Clinical Trials; Communication; Cranial Nerves; Data; Development; Distal; Embryo; Emotions; Excision; Exposure to; Eye; Eye Injuries; Face; Facial Expression; Facial Muscles; Facial Nerve Injuries; Facial nerve structure; Facial paralysis; Fluorescence; Goals; Growth Factor; Head and Neck Cancer; Head and Neck Neoplasms; Hospitalization; Human; In Vitro; Injury; Invaded; Label; Ligands; Mammals; Maps; Mental Depression; Micro Array Data; Modeling; Morbidity - disease rate; Motion; Motor Neurons; Movement; Mus; Muscle; Muscle function; Muscular Atrophy; Natural regeneration; Nerve; Nerve Regeneration; Neurons; Neurosciences; Nonverbal Communication; Olfactory Pathways; Operative Surgical Procedures; Outcome; Pain; Pathology; Patients; Pattern; Peripheral; Peripheral Nerves; Peripheral nerve injury; Persons; Positioning Attribute; Proteins; Quality of life; Rattus; Receptor Activation; Reconstructive Surgical Procedures; Recovery; Research; Signal Transduction; Site; Smiling; Social isolation; Societies; Sorting; Speed; Suicide; Supporting Cell; Synkinesis; Techniques; Testing; Translating; Translations; Trauma; Up-Regulation; Vibrissae; Work; axon growth; axon regeneration; cancer surgery; craniofacial; design; differential expression; efficacy study; functional outcomes; improved; microdevice; nerve repair; nerve supply; nerve transection; new technology; novel; novel strategies; olfactory receptor; olfactory sensory neurons; perineural; peripheral nerve regeneration; prevent; protein expression; receptor expression; receptor function; reconstruction; regenerative; sciatic nerve injury; spatiotemporal; surgery outcome; therapy development; transcriptome sequencing

ABSTRACT Injury to the facial nerve leaves the patient with limited ability to communicate with facial expression leading to reduced quality of life, depression, suicide and social isolation. The facial nerve connects to specific muscles in the face to control movement, such as the eye blink or smiling. When the facial nerve is cut it tries to regrow and reconnect to the muscles of the face, but it lacks the proper signals to guide or steer it towards the correct original muscles that it previously innervated. This incorrect rewiring leads to painful eye closure when a person wants to smile and is termed synkinesis. There are no treatments available today that can prevent synkinesis. Attempts at facial nerve reconstruction require multiple risky surgeries and lengthy hospitalizations often with limited improvements. Therefore, the objective of this project is development of novel techniques to guide facial nerve reconnection to the facial muscles and ultimately to achieve normal facial expression. To restore the original topographic organization of the facial nerve, we will first examine the expression of proteins in facial motoneuron subnuclei. Once these proteins are identified, we will then test if these proteins can guide motoneurons in microdevices simulating facial nerve branching. Following this characterization, we will design nerve grafts that act as guides for regenerating axons that contain the ligands to activate these proteins and steer the nerves towards their correct muscle target. We expect that nerve grafts with topographically positioned ligands for guidance will substantially reduce synkinesis. We will study the efficacy of these designer nerve grafts in the rat. The rat facial nerve is a well-accepted model to study facial nerve regeneration in mammals. The rat facial nerve independently controls whisker movement and eye blinking, however after injury using high speed cameras, we can precisely quantify synkinesis or extent of simultaneous blinking and whisker motion. This breakthrough would translate to patients with improved facial nerve recovery, reduced depression, and social isolation facilitating reintegration into society. The results of this work could have a path to translation into human clinical trials, as we will adapt currently used nerve grafts to contain the guidance molecules we identify in this study. This novel technology could also be readily adapted to other peripheral nerve injuries.

摘要 面部神经的损伤使病人用面部表情交流的能力受到限制 导致生活质量下降、抑郁、自杀和社会孤立。面部神经连接到特定的 面部肌肉控制运动，如眨眼或微笑。当面部神经被切断时， 再生并重新连接到面部的肌肉，但它缺乏适当的信号来引导或引导它走向 纠正以前支配的原始肌肉。这种不正确的重新布线导致痛苦的眼睛关闭时， 一个人想要微笑，这被称为联带运动。目前还没有治疗方法可以预防 联带运动面部神经重建的尝试需要多次风险手术和长期住院治疗 通常只有有限的改进。因此，本项目的目标是开发新技术， 引导面部神经重新连接到面部肌肉，并最终实现正常的面部表情。 为了恢复面神经的原始地形组织，我们将首先检查表情 面神经运动神经元亚核中的蛋白质。一旦这些蛋白质被识别，我们将测试这些蛋白质是否 可以在模拟面神经分支的微型装置中引导运动神经元。根据这一特征，我们 将设计神经移植物，作为再生轴突的指导，轴突含有激活这些配体， 蛋白质和引导神经对他们正确的肌肉目标。我们希望神经移植物 用于引导的局部定位配体将显著减少联带运动。我们将研究 这些设计师的神经移植物在老鼠身上。大鼠面神经是研究面神经的理想模型 哺乳动物的再生大鼠面神经独立控制胡须运动和眨眼， 然而，在受伤后，使用高速摄像机，我们可以精确地量化联合运动或同时运动的程度， 眨眼和胡须运动。这一突破将转化为改善面部神经恢复的患者， 减少抑郁和社会孤立，促进重新融入社会。这项工作的结果可能 这是一条转化为人类临床试验的道路，因为我们将调整目前使用的神经移植物， 我们在这项研究中发现的分子。这项新技术也可以很容易地适用于其他周围神经 受伤