Modeling of Pathogenic Breathing Pattern Dysregulation in Cardiopulmonary Disease

描述(申请人提供)：呼吸性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呼吸机支持。控制心肺功能的脑干神经回路产生振荡模式，驱动呼吸和交感运动活动。这些模式表现出高度结构化的变异性，各种慢性病患者表现出这些模式及其变异性的异常。目前还没有量化呼吸性心律失常和对严重程度或预后进行分层的分析工具，这是确定其对疾病的致病作用或开发新的非侵入性或治疗性标志物的主要障碍。这个探索性项目的长期目标是通过确定呼吸性心律失常的神经生理机制，特别是中枢(延髓)和传入(肺和气压)反馈机制之间的生理平衡来控制呼吸时相转换和模式稳定。申请者假设，这种平衡的变化在肺部疾病的病理中是明显的，但由于缺乏对呼吸控制系统动态特性的定量了解，因此处于休眠状态。这一假设将通过分析以下两个方面的呼吸模式来验证：1)Rett综合征小鼠模型，其中呼吸性心律失常主要源于中枢缺陷；2)人类肺部疾病和大鼠肺损伤模型，其中呼吸性心律失常主要源于传入反馈的改变。中心目标是开发结合呼吸模式变异性新特征的分析方法，以及准确预测由内部(例如反馈增益的网络调制、神经调节剂相互作用等)引起的呼吸节律变异性的计算模型。外部因素(外周化学感受器功能、肺力学)。一个由不同大学的四个经验丰富的小组组成的跨学科研究小组将密切合作执行这一项目。其具体目标是：1)扩展脑干呼吸网络的计算模型，不仅包括脑桥-延髓回路，还包括肺和压力反馈及其相互作用(Rybak)；2)测试新的工具，允许识别紊乱的呼吸模式(Loparo/Wilson)；3)阐明迷走神经传入激活引起的脑桥和延髓呼吸神经元突触输入相互作用的细胞机制，包括脑源性神经营养因子对脑桥-迷走神经时程控制平衡的影响(Duschmann)；4)确定正常和疾病状态下迷走神经或桥背外侧神经元的激活如何改变网络相互作用(Dick/Jacono)；以及5)描述可遗传迷走神经机制在成年双胞胎呼吸模式变异性产生中的相对作用；以及双胞胎和肺部疾病患者(Strohl/Jacono)呼吸与心脏激活的耦合(心脏排卵耦合)对呼吸变异性的影响(Strohl/Jacono)。从这一独特的合作中创建的量化工具和见解将使人们能够深入了解新的诊断、预后和治疗途径，以促进急性和慢性肺损伤的稳定呼吸并改善患者的预后。(摘要结束)

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)