Mechanisms underlying radiation-induced dysphagia

辐射引起的吞咽困难的机制

• 批准号: 10671079
• 负责人: Suzanne N. King
• 金额: $ 17.93万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671079
• 关键词: Adverse effects; Affect; Afferent Neurons; Aftercare; Area; Behavior Therapy; Behavioral; Bolus Infusion; Brain Stem; Cancer Survivor; Chemotherapy and/or radiation; Collagen; Complement; Complex; Complication; Data; Deglutition; Deglutition Disorders; Devices; Diet Modification; Eating Behavior; Enteral Feeding; Fibrosis; Functional disorder; Future; Goals; Grant; Head and Neck Cancer; Immunofluorescence Immunologic; Impairment; Injury; Intervention; Investigation; Larynx; Malnutrition; Measurement; Measures; Modality; Modeling; Motor; Motor output; Movement; Muscle; Neurons; Nociceptors; Normal tissue morphology; Oral; Oropharyngeal; Outcome; Peripheral; Pharyngeal structure; Play; Radiation; Rattus; Research; Risk; Risk Estimate; Sensory; Statistical Models; Stress; Structure of trigeminal ganglion; Sublingual Region; Testing; Therapeutic; Time; Tissues; Tongue; Trigeminal System; United States; Work; activating transcription factor 3; afferent nerve; aspirate; axon injury; behavioral outcome; chemoradiation; chemotherapy; clinically relevant; dietary restriction; drinking behavior; experimental study; head and neck cancer patient; high risk; improved; injured; irradiation; kinematics; nerve injury; neural; neural patterning; neuromechanism; neuroregulation; novel; peripheral nerve damage; predictive modeling; preservation; prevent; response; screening; sensory input; sensory integration; therapeutic target; therapeutically effective; tissue injury; treatment risk; treatment strategy; Adverse effects; Affect; Afferent Neurons; Aftercare; Area; Behavior Therapy; Behavioral; Bolus Infusion; Brain Stem; Cancer Survivor; Chemotherapy and/or radiation; Collagen; Complement; Complex; Complication; Data; Deglutition; Deglutition Disorders; Devices; Diet Modification; Eating Behavior; Enteral Feeding; Fibrosis; Functional disorder; Future; Goals; Grant; Head and Neck Cancer; Immunofluorescence Immunologic; Impairment; Injury; Intervention; Investigation; Larynx; Malnutrition; Measurement; Measures; Modality; Modeling; Motor; Motor output; Movement; Muscle; Neurons; Nociceptors; Normal tissue morphology; Oral; Oropharyngeal; Outcome; Peripheral; Pharyngeal structure; Play; Radiation; Rattus; Research; Risk; Risk Estimate; Sensory; Statistical Models; Stress; Structure of trigeminal ganglion; Sublingual Region; Testing; Therapeutic; Time; Tissues; Tongue; Trigeminal System; United States; Work; activating transcription factor 3; afferent nerve; aspirate; axon injury; behavioral outcome; chemoradiation; chemotherapy; clinically relevant; dietary restriction; drinking behavior; experimental study; head and neck cancer patient; high risk; improved; injured; irradiation; kinematics; nerve injury; neural; neural patterning; neuromechanism; neuroregulation; novel; peripheral nerve damage; predictive modeling; preservation; prevent; response; screening; sensory input; sensory integration; therapeutic target; therapeutically effective; tissue injury; treatment risk; treatment strategy

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.

抽象的 辐射引起的吞咽困难是头颈化学放疗治疗的毁灭性并发症 癌症。吞咽过程中口服和咽部运动的缺陷是辐射的最普遍原因 诱发吞咽困难。这些吞咽问题的不利影响会导致长期饮食 限制，营养不良和放置喂食管以防止抽吸。最近的证据 身体的区域表明，辐射会损害周围神经，导致电动机变化 功能。但是，辐射引起的吞咽困难的基础神经机制尚不清楚。一个 需要了解辐射引起的吞咽困难的病理生理学才能发展更有效 旨在保存化学放疗后吞咽功能的治疗靶标。吞咽是协调的 由脑干中神经模式产生电路控制的活动，严重依赖感官 信息。伤害感受器是通过组织损伤敏感的感觉神经元的子集。当伤害感受器 感官轴突受损，它们会触发保护性反应，可以推动神经控制的变化。 在协调的电动机输出中的干扰。我们建议伤害感受器的活动干扰吞咽 化学放疗肌肉损伤后功能可能是另一个潜在的机制。在提议中 研究，我们将表征口咽吞咽如何受到化学的影响并确定 感觉神经元的损伤是否会导致治疗后吞咽困难。我们假设这一点 化学放疗诱导的轴突损伤与口服和咽吞咽运动学的变化有关 治疗后。这项研究具有两个特定的目标，这些目标得到了初步数据的强烈支持。在目标1中 我们将确定化学放疗对肌羟基肌肉对口腔运动的影响 吞咽过程中的咽结构。运动学分析和力量测量将用于量化 功能不足。在AIM 2中，我们将确定三叉神经中诱导的神经损伤/压力样反应 对肌羟基化学放疗后的感觉神经元。我们将在 三叉神经节从肌羟基投射并测量其损伤/应力诱导的表达 标记。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 治疗组织和行为结果的风险。提出的实验将确定 基于辐射引起的吞咽困难的基于新型神经的机制，并定义了特定点 大鼠化学放疗后吞咽功能障碍将作为评估未来治疗的靶标。