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的呼吸系统疾病中起致病作用，包括睡眠呼吸暂停、急性肺损伤和慢性肺部疾病的通气支持。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可变性，患有各种慢性疾病的患者表现出这些模式及其可变性的畸变。目前还没有量化通气性心律失常和严重程度或预后分层的分析工具，这是确定其致病因素或开发新的非侵入性或治疗性标志物的主要障碍。本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机制，特别是中枢（桥髓）和传入（肺和气压）反馈机制在控制呼吸相转换和模式稳定中的生理平衡来实现这些目标。申请人假设这种平衡的改变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理解而处于休眠状态。这一假设将通过分析呼吸模式来验证：1)Rett综合征小鼠模型，其中通气性心律失常主要源于中枢功能缺陷；2)肺部疾病患者和肺损伤大鼠模型，其中通气性心律失常主要源于传入反馈改变。中心目标是发展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）和外部因素（外周化学感受器功能，肺力学）引起的呼吸节奏变异性的计算模型。一个跨学科的研究团队，包括来自不同大学的四个经验丰富的小组，将密切合作来执行这个项目。具体目标是：1)扩展脑干呼吸网络的计算模型，不仅包括桥-髓回路，还包括肺和气压反馈及其相互作用（Rybak）；2)测试允许识别紊乱呼吸模式的新工具（Loparo/Wilson）；3)阐明迷走神经传入激活引起的脑桥和髓质呼吸神经元突触输入参与桥-迷走神经相互作用的细胞机制，包括脑源性神经营养因子对桥-迷走神经相时控制平衡的影响（Dutschmann）；4)确定正常和疾病状态下迷走神经或脑桥背外侧神经元的激活如何改变网络相互作用（Dick/Jacono）；5)描述遗传迷走神经机制在产生成年双胞胎呼吸模式变异中的相对作用；以及通气耦合对心脏激活（心血管耦合）对双胞胎和肺病患者呼吸变异性的影响（Strohl/ Jacono）。这种独特的合作创造的定量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，以促进呼吸稳定，改善急性和慢性肺损伤患者的预后。（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)