A Rodent Model of Compromised Upper Airway

受损上呼吸道的啮齿动物模型

基本信息

批准号：
7789600
负责人：
LESZEK K KUBIN
金额：
$ 23.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2011-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7789600
关键词：
Accidents Accounting Acute Address Adrenergic Agents Adult Affect Affective Airway Resistance American Anatomy Animal Model Animals Automobile Driving Behavior Breathing Cardiovascular system Characteristics Chronic Cognitive Dependence Developed Countries Disease Exhibits Exposure to Genetic Goals Hour Human Hyoid bone structure Hypertension Hypoxemia Hypoxia Insulin Resistance Lead Legal patent Maintenance Measures Mediating Metabolic Modeling Monitor Motor Motor Neurons Muscle Muscle Tonus Obesity Obstruction Obstructive Sleep Apnea Operative Surgical Procedures Patients Physiological Play Process Rattus Relative (related person)Risk Rodent Rodent Model Role Severities Sleep Sleep Fragmentations Structure System Testing Thyroid cartilage structure Time Wakefulness Workplace adrenergic airway obstruction base bone cost density instrument nerve supply neurochemistry neuroregulation noradrenergic novel pressure prevent productivity loss public health relevance receptor research study response soft tissue tool

项目摘要

DESCRIPTION (provided by applicant): The obstructive sleep apnea syndrome (OSA) affects 3-5% of adults. The disorder is manifest by recurring episodes of upper airway narrowing and obstruction that occur exclusively during sleep. Underlying the disorder is altered anatomy of the upper airway that allows the soft tissues surrounding the airway lumen to collapse under the centripetal force of the negative inspiratory pressure, which leads to airway obstruction. OSA subjects adapt to this anatomical vulnerability by generating a higher level of activity in their upper airway dilating muscles than that in healthy subjects, but the cellular and systemic mechanisms underlying this adaptation are unknown and cannot be determined due to lack of a suitable animal model. The goal of this project is to develop and conduct initial characterization of what may prove to be the first rodent model of compromised upper airway in which, like in OSA patients, the animal adapts to weakened muscular support of the upper airway by increasing its upper airway motor tone. Our preliminary experiments show that severing the attachment of the geniohyoid and hyoglossus (GH/GH) muscles to the hyoid (H) bone makes less negative the critical pressure at which the airway collapses and increases the level of activity in the genioglossus (GG), the main muscle that protects the airway from collapse in humans. Based on these encouraging initial results, we propose a study with the following two Specific Aims. (1) Determine whether, in chronically instrumented, behaving rats, surgically weakened support of the upper airway leads to a compensatory increase in GG muscle activity. We shall quantify the tonic, phasic-inspiratory and total GG activity in rats that will have different degrees of permanent detachment of the GH/HG from the H-bone and those in which a re-attachment will be allowed to occur. In parallel acute experiments, we will determine the impact of the same surgical intervention on airway resistance and collapsibility. (2) Determine whether surgically weakened support of the upper airway in rats that exhibit increased upper airway motor tone is associated with increased density of noradrenergic and serotonergic innervation of hypoglossal (XII) motoneurons that control the GG and/or increased expression of excitatory aminergic receptors (type 2 serotonergic and 11 adrenergic) that were previously identified as playing a key role in mediating state-dependent excitatory drive to XII motoneurons. The project will characterize a novel, rodent-based, model of upper airway control that mimics the adaptive processes that may be similar to those in OSA patients. This should offer new means of investigating the mechanisms underlying the adaptive increase in upper airway motor tone in OSA patients. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea syndrome (OSA) is a debilitating disorder affecting 3-5% of adult Americans. To maintain adequate breathing during wakefulness, OSA patients adapt to the compromised anatomy of their upper airway, but the mechanisms underlying this adaptation are unknown. Our goal is to establish a novel rodent model of compromised upper airway in which, like in OSA patients, upper airway motor tone is increased in response to a surgical intervention that weakens the muscular support of the airway. We will characterize the model and determine whether the adaptation is associated with changes in the central control of the motor neurons that innervate the genioglossus, an important muscle that protects the airway from collapse. The study will provide a new tool with which to investigate the pathophysiological mechanisms of OSA.

描述（由申请人提供）： 3-5% 的成年人患有阻塞性睡眠呼吸暂停综合征 (OSA)。该疾病的表现为仅在睡眠期间反复发作的上呼吸道狭窄和阻塞。这种疾病的根本原因是上呼吸道解剖结构的改变，导致气道管腔周围的软组织在吸气负压的向心力作用下塌陷，从而导致气道阻塞。 OSA 受试者通过在上呼吸道扩张肌肉中产生比健康受试者更高水平的活动来适应这种解剖学脆弱性，但这种适应背后的细胞和系统机制尚不清楚，并且由于缺乏合适的动物模型而无法确定。该项目的目标是开发并初步表征可能被证明是第一个上呼吸道受损的啮齿动物模型，在该模型中，与 OSA 患者一样，动物通过增加上呼吸道来适应上呼吸道肌肉支持减弱的情况电机音。我们的初步实验表明，切断颏舌骨和舌骨 (GH/GH) 肌肉与舌骨 (H) 的附着可以减少气道塌陷时的临界压力，并增加颏舌肌 (GG) 的活动水平，保护人类气道免于塌陷的主要肌肉。基于这些令人鼓舞的初步结果，我们提出了一项具有以下两个具体目标的研究。 (1) 确定在长期使用仪器、表现良好的大鼠中，手术削弱上呼吸道支持是否会导致 GG 肌肉活动代偿性增加。我们将量化大鼠中的强直、阶段性吸气和总 GG 活性，这些大鼠将具有不同程度的 GH/HG 从 H 骨永久分离以及允许发生重新附着的大鼠。在并行的急性实验中，我们将确定相同的手术干预对气道阻力和塌陷性的影响。 (2) 确定上气道运动音调增加的大鼠上气道支撑的手术减弱是否与控制 GG 的舌下 (XII) 运动神经元的去甲肾上腺素能和血清素能神经支配密度增加和/或兴奋性胺能受体表达增加有关（2 型血清素能和 11 型肾上腺素能）先前被认为在调节中发挥关键作用XII 运动神经元的状态依赖性兴奋性驱动。该项目将描述一种基于啮齿动物的新型上呼吸道控制模型，该模型模仿可能与 OSA 患者相似的适应性过程。这应该为研究 OSA 患者上呼吸道运动张力适应性增加的机制提供新的方法。公共健康相关性：阻塞性睡眠呼吸暂停综合征 (OSA) 是一种使人衰弱的疾病，影响 3-5% 的美国成年人。为了在清醒时保持充足的呼吸，OSA 患者会适应上呼吸道受损的解剖结构，但这种适应的机制尚不清楚。我们的目标是建立一种新型的上气道受损的啮齿动物模型，其中，与 OSA 患者一样，上气道运动张力会因手术干预而增加，从而削弱气道的肌肉支持。我们将描述该模型的特征，并确定这种适应是否与支配颏舌肌的运动神经元的中央控制变化有关，颏舌肌是保护气道免于塌陷的重要肌肉。该研究将为研究 OSA 的病理生理机制提供新的工具。