Mechanisms underlying radiation-induced dysphagia

摘要 放射性吞咽困难是头颈部放化疗的破坏性并发症 癌症。吞咽过程中口腔和咽部运动障碍是最常见的辐射原因- 导致吞咽困难。这些吞咽问题的不良影响可能导致长期饮食。 限制、营养不良和放置喂养管以防止吸入。最近在其他方面的证据 身体的某些部位表明，辐射会损害周围神经，导致运动功能改变。 功能。然而，放射性吞咽困难的神经机制尚不清楚。一个 需要了解放射性吞咽困难的病理生理学，才能开发出更有效的方法。 旨在保留放化疗后吞咽功能的治疗靶点。吞咽是一种协调的 由脑干中严重依赖感觉的神经模式产生电路控制的活动 信息。伤害性感受器是感觉神经元的一个子集，由组织损伤敏化。当痛觉感受器 感觉轴突受损，它们会触发保护性反应，从而推动神经控制主导的变化 协调电机输出中的干扰。我们认为伤害性感受器活动干扰吞咽 功能可能是放化疗肌肉损伤后发挥作用的另一个潜在机制。在建议的 研究，我们将表征口咽部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 放化疗引起的轴突损伤与口腔和咽部吞咽运动学的改变有关 治疗后。这项研究有两个明确的目标，初步数据有力地支持了这两个目标。在目标1中 我们将确定对舌骨肌进行化疗对口腔和下颌骨运动的影响。 吞咽时的咽部结构。将使用运动学分析和力测量来量化 功能缺陷。在目标2中，我们将确定三叉神经神经损伤/应激样反应。 舌骨肌化疗后的感觉神经元。我们将识别大脑中的感觉神经元 三叉神经节从舌骨突起及其在损伤/应激反应中的表达 记号笔。我们还将测试替代机制，并开发一个预测模型来量化并发症 治疗对组织和行为结果的风险。拟议的实验将确定一种 辐射诱发吞咽困难的新的神经机制和确定特定的穴位 放化疗后大鼠的吞咽功能障碍，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.