Mechanisms underlying radiation-induced dysphagia

摘要 放射性吞咽困难是头颈部放化疗的一种严重并发症 癌吞咽时口腔和咽部运动的缺陷是辐射的最常见原因- 引起吞咽困难这些吞咽问题的不良影响可能会导致长期的饮食 限制、营养不良和放置喂食管以防止误吸。其他方面的最新证据 身体的某些区域表明，辐射可损伤周围神经，导致运动神经的变化。 功能然而，辐射引起的吞咽困难的神经机制是未知的。一个 需要了解放射性吞咽困难的病理生理学， 治疗目标旨在保留放化疗后吞咽功能。吞咽是一种协调的 由脑干中的神经模式生成电路控制的活动，该电路严重依赖于感觉 信息.伤害感受器是由组织损伤致敏的感觉神经元的子集。当伤害感受器 当感觉轴突受损时，它们触发保护性反应，可以驱动神经控制的变化， 协调电机输出的干扰。我们认为伤害感受器活动干扰吞咽 功能可能是放化疗后肌肉损伤的另一个潜在机制。拟议 研究中，我们将描述口咽吞咽如何受到放化疗的影响，并确定 感觉神经元损伤是否会导致治疗后吞咽困难。我们假设 放化疗诱导的轴突损伤与口腔和咽部吞咽运动学的变化相关 治疗后这项研究有两个具体目标，得到了初步数据的有力支持。目标1 我们将确定化放疗对下颌舌骨肌的影响， 吞咽时的咽部结构。运动学分析和力测量将用于量化 功能缺陷在目标2中，我们将确定在三叉神经中诱导的神经损伤/应激样反应。 感觉神经元后的放化疗下颌舌骨肌。我们将在大脑皮层中识别感觉神经元， 三叉神经节突出的下颌舌骨和测量他们的表达损伤/应力诱导 标记。我们还将测试替代机制并开发预测模型来量化并发症 治疗对组织和行为结果的风险。拟议的实验将建立一个可行性的 新的基于神经的机制，辐射诱导的吞咽困难，并确定具体点， 大鼠放化疗后吞咽功能障碍，将作为评估未来治疗的目标。

ABSTRACT Radiation-induced dysphagia is a devastating complication of chemoradiation treatment for head and neck cancer. Deficits in oral and pharyngeal movement during swallowing are the most prevalent cause of radiation- induced dysphagia. The adverse effects of these swallowing problems can lead to long-term dietary restrictions, malnutrition, and placement of a feeding tube to prevent aspiration. Recent evidence in other areas of the body demonstrate that radiation can damage peripheral nerves resulting in changes in motor function. However, the neural mechanisms underlying radiation-induced dysphagia are unknown. An understanding of the pathophysiology of radiation-induced dysphagia is needed to develop more effective therapeutic targets aimed at preserving post chemoradiation swallowing function. Swallowing is a coordinated activity controlled by a neural pattern-generating circuitry in the brainstem that relies heavily on sensory information. Nociceptors are a subset of sensory neurons that are sensitized by tissue injury. When nociceptor sensory axons are damaged, they trigger protective responses that can drive changes in neural control leading to disturbances in coordinated motor output. We propose that nociceptor activity interfering with swallowing function may be another potential mechanism at play after chemoradiation muscle injury. In the proposed study, we will characterize how oropharyngeal swallowing is affected by chemoradiation and determine whether injury of sensory neurons can contribute to dysphagia post-treatment. We hypothesize that chemoradiation-induced axon injury is associated with changes in oral and pharyngeal swallowing kinematics after treatment. This research has two specific aims that are strongly supported by preliminary data. In Aim 1 we will determine the effect of chemoradiation to the mylohyoid muscle on the movement of the oral and pharyngeal structures during swallowing. Kinematic analysis and force measures will be used to quantify functional deficits. In Aim 2 we will determine the nerve injury/stress-like response induced in trigeminal sensory neurons following chemoradiation to the mylohyoid muscle. We will identify sensory neurons in the trigeminal ganglion projecting from the mylohyoid and measure their expression of injury/stress-induced markers. We will also test alternative mechanisms and develop a predictive model to quantify the complication risk of treatment to tissue and behavioral outcomes. The proposed experiments will establish the feasibility of a novel neural-based mechanism underlying radiation-induced dysphagia and define specific points of swallowing dysfunction after chemoradiation in the rat that will serve as targets for assessing future treatments.