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.

抽象的 面部神经的伤害使患者与面部表情交流的能力有限 导致生活质量降低，抑郁，自杀和社会隔离。面神经连接到特定 脸上的肌肉控制运动，例如眼睛眨眼或微笑。切割面神经时，它会尝试 重新生长并重新连接到脸部的肌肉，但缺乏适当的信号来指导或转向 纠正先前支配的原始肌肉。这种不正确的重新布线会导致痛苦的闭眼 人想微笑，被称为同步性。今天没有可用的治疗方法可以防止 伙伴。面部神经重建的尝试需要多次危险的手术和漫长的住院治疗 通常有限的改进。因此，该项目的目的是开发新技术 引导面神经重新连接到面部肌肉，并最终达到正常的面部表达。 为了恢复面神经的原始地形组织，我们将首先检查表达 面部运动神经元亚核中蛋白质的蛋白质。一旦确定了这些蛋白质，我们将测试这些蛋白质是否 可以指导模拟面部神经分支的微型版本中的运动神经元。遵循此特征，我们 将设计神经移植物，充当重生轴突的指南，该轴突包含配体激活这些配体 蛋白质并将神经转向其正确的肌肉靶标。我们期望神经移植 地形定位的配体进行指导将大大减少同步性。我们将研究功效 在大鼠中的这些设计师神经移植物中。大鼠面神经是研究面神经的良好模型 哺乳动物的再生。大鼠面神经独立控制晶须运动和眼睛闪烁， 但是，使用高速摄像机受伤后，我们可以精确量化同步性或同时范围 眨眼和晶须运动。这一突破将转化为面部神经恢复改善的患者， 减少抑郁症，社会隔离促进了重新融入社会。这项工作的结果可能有 转化为人类临床试验的途径，因为我们将适应当前使用神经移植物来包含指导 我们在这项研究中识别的分子。这种新颖的技术也很容易适应其他外围神经 受伤。