Modeling of Pathogenic Breathing Pattern Dysregulation in Cardiopulmonary Disease

心肺疾病致病性呼吸模式失调的建模

• 批准号: 7864085
• 负责人: KINGMAN PERKINS STROHL
• 金额: $ 25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7864085
• 关键词: Acute; Acute Lung Injury; Adult; Age; Algorithms; Arrhythmia; Award; Brain Stem; Brain-Derived Neurotrophic Factor; Breathing; Cardiac; Cardiopulmonary; Characteristics; Chemoreceptors; Chest wall structure; Chronic; Chronic Disease; Chronic lung disease; Collaborations; Computer Simulation; Coupling; Data; Data Set; Development; Disease; Doctor of Philosophy; Equilibrium; Exhibits; Feedback; Grant; Heart failure; Human; Interdisciplinary Study; Lead; Lung; Lung diseases; Measurement; Mechanics; Modeling; Motor Activity; Neuromodulator; Neurons; Outcome; Patients; Pattern; Peripheral; Phase; Phenotype; Physiological; Play; Pontine structure; Property; Protocols documentation; Pulmonary Heart Disease; Pulmonary Pathology; Rattus; Records; Recruitment Activity; Relative (related person); Reporting; Respiration Disorders; Respiratory physiology; Rett Syndrome; Role; Severities; Sleep Apnea Syndromes; Stratification; Structure; Study Subject; Subgroup; Synapses; System; Testing; Therapeutic; Time; TimeLine; Twin Multiple Birth; Universities; abstracting; analytical method; base; esophagus pressure; experience; human subject; improved; insight; lung injury; mouse model; neural circuit; novel; novel diagnostics; outcome forecast; prognostic; respiratory; tool

DESCRIPTION (provided by applicant): Ventilatory arrhythmia plays a pathogenic role in many common respiratory disorders ranging from sleep apnea, and acute lung injury to ventilatory support in the setting of chronic lung disease. Brainstem neural circuits that control cardiopulmonary functions generate oscillatory patterns that drive respiratory as well as sympathetic motor activities. These patterns exhibit highly structured variability and patients with various chronic diseases exhibit aberrations of these patterns and their variabilities. Analytic tools for quantifying ventilatory arrhythmia and for stratification of severity or prognosis are unavailable, representing a major barrier to defining its pathogenic contribution to disease, or to developing novel non-invasive or therapeutic markers. The long-term objectives of this exploratory project are these targets by determining the neurophysiologic mechanisms for ventilatory arrhythmia, specifically the physiological balance between central (pontomedullary) and afferent (pulmonary and baro) feedback mechanisms in the control of respiratory phase switching and pattern stabilization. The applicants hypothesize that alterations in this balance are evident in the pathology of the pulmonary conditions, but lie dormant due to lack of quantitative understanding of the dynamic properties of the respiratory control system. This hypothesis will be tested by analyzing breathing patterns in: 1) a mouse model of Rett syndrome, in which ventilatory arrhythmia originates primarily from central deficits and 2) in humans with lung disease and a rat model of lung injury, in which ventilatory arrhythmia originates primarily from altered afferent feedback. The central aim is to develop analytical methods that incorporate new characteristics of breathing pattern variability, and a computational model that accurately predicts respiratory rhythm variability resulting from internal (e.g. network modulation of feedback gain, neuromodulator interactions etc.) and external factors (peripheral chemoreceptor function, lung mechanics). An interdisciplinary research team that includes four experienced groups at different Universities will collaborate closely to perform this project. The specific aims are: 1) to expand a computational model of the brainstem respiratory network to include not only the ponto-medullary circuits but pulmonary and baro-feedback and their interactions (Rybak); 2) to test novel tools permitting the identification of disturbed breathing patterns (Loparo/Wilson); 3) to elucidate the cellular mechanisms involved in reciprocal ponto-vagal interactions by synaptic inputs to pontine and medullary respiratory neurons elicited by vagal afferent activation, including an influence of brain derived neurotrophic factor on the balance of pontine-vagal control of phase duration (Dutschmann); 4) to determine how the network interactions are altered by activation of vagal or dorsolateral pontine neurons in normal and disease states (Dick/Jacono); and 5) to describe the relative role of heritable vagal mechanisms in generating breathing pattern variability in adult twins; and the impact of ventilatory coupling to cardiac activation (cardioventilatory coupling) on breathing variability in twins and patients with lung disease (Strohl/ Jacono). The quantitative tools and insights created from this unique collaboration will permit insight into new diagnostic, prognostic and therapeutic avenues to promote stable breathing and improve patient outcomes in acute and chronic lung injury. (End of Abstract)

描述（由申请人提供）：通气心律失常在许多常见的呼吸系统疾病中起致病作用，从睡眠呼吸暂停，急性肺损伤到慢性肺部疾病的通气损伤。控制心肺功能的脑干神经回路会产生振荡模式，驱动呼吸道以及交感神经活动。这些模式表现出高度结构化的变异性，患有各种慢性疾病的患者表现出这些模式及其变异性的畸变。量化通气性心律失常和严重性或预后分层的分析工具是无法获得的，这是定义其对疾病的致病性贡献或发展新颖的非侵入性或治疗标记的主要障碍。该探索性项目的长期目标是通过确定通气心律不齐的神经生理机制，特别是中枢（Pontomedullary）与传入（肺和巴罗）反馈机制之间的生理平衡，以控制呼吸相位切换和稳定性。申请人假设这种平衡的改变在肺部条件的病理中很明显，但是由于缺乏对呼吸控制系统动态特性的定量理解，由于缺乏定量的理解而处于休眠状态。该假设将通过分析呼吸模式进行检验：1）RETT综合征的小鼠模型，其中通气性心律不齐主要起源于中心缺陷，而2）患有肺部疾病的人和肺损伤的大鼠模型，其中通气性心律失常起源于该模型主要来自变化的传入反馈。核心目的是开发融合呼吸模式变异性新特征的分析方法，以及一种计算模型，该模型准确预测由内部（例如，反馈增益网络调制，神经调节剂相互作用等）和外部因素（外周化学感受器功能）引起的呼吸节奏变异性，肺力学）。一个跨学科研究团队在不同的大学中包括四个经验丰富的小组，将密切合作以执行该项目。具体目的是：1）扩展脑干呼吸网络的计算模型，不仅包括蓬托 - 梅医学回路，还包括肺和巴罗反馈及其相互作用（RYBAK）； 2）测试新工具，允许识别受干扰的呼吸模式（Loparo/Wilson）； 3）阐明通过迷走神经传播激活引发的突触输入到蓬蒂因和髓质呼吸神经元的相互蓬托相互作用所涉及的细胞机制，包括大脑衍生神经营养因子对脑源性神经营养因子的影响（脑源性神经营养因子对庞然大物的平衡的影响） ）； 4）确定在正常和疾病状态下的迷走神经或背外侧蓬托神经元的激活（Dick/Jacono）如何改变网络相互作用； 5）描述可遗传迷走神经机制在成年双胞胎中产生呼吸模式变异性方面的相对作用；以及通气耦合与心脏激活（心脏替代耦合）对双胞胎和肺部疾病患者呼吸变异性（Strohl/ Jacono）的影响。通过这种独特的合作创造的定量工具和见解将使您可以深入了解新的诊断，预后和治疗性途径，以促进稳定的呼吸并改善急性和慢性肺损伤的患者结果。 （抽象的结尾）

项目成果

Breathing irregularity during wakefulness associates with CPAP acceptance in sleep apnea.

清醒时的呼吸不规律与睡眠呼吸暂停中 CPAP 的接受程度相关。

• DOI: 10.1007/s11325-012-0775-2
• 发表时间: 2013
• 期刊: Sleep Breath
• 影响因子: 2.5
• 作者: Yamauchi M;Jacono FJ;Fujita Y;Yoshikawa M;Ohnishi Y;Nakano H;Campanaro CK;Loparo KA;Strohl KP;Kimura H.
• 通讯作者: Kimura H.

Effects of environment light during sleep on autonomic functions of heart rate and breathing.

睡眠时环境光对心率和呼吸自主功能的影响。

• DOI: 10.1007/s11325-014-0951-7
• 发表时间: 2014
• 期刊: Sleep Breath
• 影响因子: 2.5
• 作者: Yamauchi M;Jacono FJ;Fujita Y;Kumamoto M;Yoshikawa M;Campanaro CK;Loparo KA;Strohl KP;Kimura H.
• 通讯作者: Kimura H.