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起致病作用，范围从睡眠呼吸暂停和急性肺损伤到慢性肺病背景下的呼吸支持。控制心肺功能的脑干神经回路产生驱动呼吸以及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。用于定量解释性心律失常和用于严重程度或预后分层的分析工具是不可用的，这代表了定义其对疾病的致病贡献或开发新的非侵入性或治疗标记物的主要障碍。该探索性项目的长期目标是通过确定诱发性心律失常的神经生理机制来实现这些目标，特别是在控制呼吸相位转换和模式稳定中中枢（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。将通过分析以下模型中的呼吸模式来检验该假设：1）Rett综合征小鼠模型，其中诱发性心律失常主要源于中枢缺陷; 2）肺病患者和肺损伤大鼠模型，其中诱发性心律失常主要源于传入反馈改变。中心目标是开发分析方法，其结合呼吸模式变异性的新特征，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。和外部因素（外周化学感受器功能、肺力学）。一个跨学科的研究团队，其中包括四个经验丰富的团体在不同的大学将密切合作，以执行这个项目。具体目标是：1）扩展脑干呼吸网络的计算模型，不仅包括脑桥-延髓回路，还包括肺和气压反馈及其相互作用（Rybak）; 2）测试允许识别干扰呼吸模式的新工具（Loparo/Wilson）; 3）阐明相互桥脑的细胞机制，迷走神经传入激活引起的对脑桥和延髓呼吸神经元的突触输入的迷走神经相互作用，包括脑源性神经营养因子对脑桥-迷走神经控制相时程平衡的影响（Dutschmann）; 4）确定在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）;和5）描述可遗传的迷走神经机制在成年双胞胎中产生呼吸模式变异性的相对作用;以及双胞胎和肺部疾病患者中心脏激动的呼吸耦合（心脏呼吸耦合）对呼吸变异性的影响（Strohl/ Jacono）。从这种独特的合作中产生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，以促进稳定的呼吸并改善急性和慢性肺损伤患者的预后。 (End摘要）

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)