Ectopic Olfactory Receptor Guided Facial Nerve Regeneration

摘要 面部神经损伤使患者与面部表情的交流能力有限 导致生活质量下降、抑郁、自杀和社会孤立。面神经连接到特定的 面部肌肉控制运动，如眨眼或微笑。当面神经被切断时，它试图 再生并重新连接到面部肌肉，但它缺乏适当的信号来引导或引导它朝向 纠正它先前神经支配的原始肌肉。这种不正确的重新布线会导致痛苦的闭眼 人想笑，被称为联想症。目前还没有可用的治疗方法可以预防 联体运动。面神经重建的尝试需要多次危险的手术和漫长的住院 通常只有有限的改进。因此，该项目的目标是开发新的技术来 引导面神经重新连接到面部肌肉，最终达到正常的面部表情。 为了恢复面神经的原始地形图组织，我们首先检查表情 面部运动神经元亚核中的蛋白质。一旦鉴定出这些蛋白质，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设备中引导运动神经元。根据这一特征，我们 将设计神经移植物，作为再生轴突的向导，这些轴突含有激活这些配体的配体 蛋白质并引导神经朝向正确的肌肉目标。我们预计神经移植物与 用于制导的地形性配基将大大减少联动。我们将研究其疗效 这些精心设计的神经移植物在老鼠身上。大鼠面神经是目前公认的研究面神经的模型。 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，在损伤后，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。这一突破将转化为面神经恢复改善的患者， 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是 一条转化为人类临床试验的途径，因为我们将调整目前使用的神经移植物来包含指导 我们在这项研究中确定的分子。这项新技术也可以很容易地适用于其他周围神经 受伤。

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.