Modeling of Pathogenic Breathing Pattern Dysregulation in Cardiopulmonary Disease

描述（由申请人提供）：通气性心律失常在许多常见呼吸系统疾病中发挥致病作用，从睡眠呼吸暂停、急性肺损伤到慢性肺病情况下的通气支持。控制心肺功能的脑干神经回路产生驱动呼吸和交感运动活动的振荡模式。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。目前还没有用于量化通气性心律失常以及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型非侵入性或治疗性标记物的主要障碍。该探索性项目的长期目标是通过确定通气性心律失常的神经生理学机制来实现这些目标，特别是控制呼吸相位切换和模式稳定的中枢（脑桥延髓）和传入（肺和气压）反馈机制之间的生理平衡。申请人假设这种平衡的改变在肺部病症的病理学中是明显的，但由于缺乏对呼吸控制系统的动态特性的定量理解而处于休眠状态。该假设将通过分析以下呼吸模式来检验：1）雷特综合征小鼠模型，其中通气性心律失常主要源于中枢缺陷；2）患有肺病的人类和肺损伤大鼠模型，其中通气性心律失常主要源于传入反馈改变。中心目标是开发结合呼吸模式变异新特征的分析方法，以及准确预测由内部（例如反馈增益的网络调制、神经调节器相互作用等）和外部因素（外周化学感受器功能、肺力学）引起的呼吸节律变异的计算模型。由来自不同大学的四个经验丰富的小组组成的跨学科研究团队将密切合作来执行该项目。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，还包括肺反馈和气压反馈及其相互作用（Rybak）； 2) 测试能够识别呼吸紊乱模式的新颖工具（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参与桥脑-迷走神经相互相互作用的细胞机制，包括脑源性神经营养因子对桥脑-迷走神经相持续时间控制平衡的影响（Dutschmann）； 4）确定正常和疾病状态下迷走神经或背外侧脑桥神经元的激活如何改变网络相互作用（Dick/Jacono）； 5) 描述遗传性迷走神经机制在成年双胞胎呼吸模式变异中的相对作用；以及通气耦合与心脏激活（心通气耦合）对双胞胎和肺病患者呼吸变异性的影响（Strohl/Jacono）。通过这种独特的合作创建的定量工具和见解将有助于深入了解新的诊断、预后和治疗途径，以促进稳定呼吸并改善急性和慢性肺损伤患者的治疗结果。 （摘要完）

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)