A complex systems approach to bronchoconstriction in Asthma

描述（由申请人提供）：哮喘是一种发病率迅速增加的疾病，仅在美国就影响超过1700万人。了解不均匀通气和气道阻塞的原因是非常重要的，这是哮喘肺功能障碍的主要特征。然而，尽管对单个气道的行为以及哮喘的细胞和分子机制有详细的了解，但对哮喘气道树的异质性收缩的原因知之甚少。我们的工作假设是，在哮喘中观察到的通气和气道阻塞的异质性，是一个复杂网络的紧急行为的表达，该网络放大了单个气道结构或功能的空间异质性的影响。在这个项目中，我们建议应用复杂系统研究的分析工具来分析肺在稳态和非稳态条件下的综合网络模型的行为。该项目涉及计算机建模和PET-CT成像研究的结合使用，重点关注两个主要的具体目标，每个目标都涉及理论和实验方面：SA 1：确定导致肺部从均匀状态到异质状态的关键转变的条件，并根据现有和新的实验数据校准理论预测。SA 2：阐明肺的动态行为及其历史是否可以使系统处于异常的异质状态，以及是否可以使用某些干预措施将系统重置为正常的均匀状态。该项目挑战了哮喘研究的现有范式，并提出了一种新的综合生理系统方法来解决这个问题。我们认为，这种方法是朝着提高对该病的了解迈出的重要一步，而这种了解是开发诊断和治疗该病的创新方法所必需的。这些研究的一个更广泛的目标是提供理论和实验证据，以支持J. H. T. Bates最近提出的一种关于复杂疾病的新理论（17），即反复暴露于侮辱会使系统处于异常状态，一旦侮辱源被移除，系统可能不会自发地恢复正常。这项研究具有很高的杠杆作用，因为它将导致开发一般复杂系统工具，用于治疗像肺这样的系统，这些系统以具有双稳态元素的分层网络为特征。公共卫生相关性：

DESCRIPTION (provided by applicant): Asthma is a disease of rapidly increasing incidence that affects more than 17 million people in the United States alone. It is of major importance to understand the causes of heterogeneous ventilation and airway obstruction, cardinal features responsible for lung dysfunction in asthma. Yet, despite detailed knowledge of the behavior of individual airways, and of cellular and molecular mechanism of asthma, not much is known about why the asthmatic airway tree constricts heterogeneously. Our working hypothesis is that heterogeneity of ventilation and airway obstruction observed in asthma, is an expression of emergent behavior of a complex network that magnifies the effects of spatial heterogeneity in structure or function of individual airways. In this project we propose to apply analytical tools from complex systems research to analyze the behavior of an integrative network model of the lung under both steady and unsteady conditions. The project involves the combined use of computational modeling and imaging studies using PET-CT focused on two major specific aims, each involving theoretical and experimental aspects: SA 1: Identify the conditions leading to a critical transition in the lungs from a uniform to a heterogeneous state, and calibrate theoretical predictions against existing and new experimental data. SA 2: Elucidate whether the dynamic behavior of the lung and its history can trap the system in abnormal heterogeneous states, and whether certain interventions can be used to reset the system back to a normal uniform state. This project challenges existing paradigms in asthma research and proposes a novel integrated physiological systems approach to the problem. This approach, we feel, is a vital step towards improved understanding of the disease that is needed for development of innovative methods to its diagnosis and therapy. A broader objective of these studies is to provide theoretical and experimental evidence in support of a novel theory on complex diseases recently formulated by J. H. T. Bates (17) whereby repeated exposure to insults could trap the system in abnormal states from which return to normality may not spontaneously occur once the insult source is removed. The research is highly leveraged, as it will lead to development of general complex systems tools for treating systems that, like the lung, are characterized by hierarchical networks with bistable elements. PUBLIC HEALTH RELEVANCE: Asthma is a disease of multiple origins that is becoming increasingly common and affects more than 300 million people worldwide with an estimated total economic burden of $6 billion annually. Predicting the timing and severity of an asthma attack is important to avoid life-threatening situations. This research is aimed at understanding the complex behavior of the lungs during an asthma attack, a key step needed for developing and testing therapeutic interventions to prevent or reverse asthma attacks.