Airway Hyper-responsiveness: from molecule to organ

概述：哮喘肺通常对吸入过敏原有反应，气道功能明显降低。这种现象被称为气道高反应性（AHR），可能危及生命。AHR不是一个简单的反应，而是在巨大的长度和时间尺度上表现出来的多个过程的高潮。在一个极端，分子信号和相互作用决定了气道平滑肌细胞（ASMCs）产生的力。在另一个极端，asmc的收缩转化为分支气道的动态和复杂的收缩，患者通过增加呼吸困难来感知。此外，哮喘治疗主要是药物治疗，在分子水平上起作用，但临床结果是在整个肺水平上测量的。这两个极端是由许多中等规模的事件联系在一起的。AHR的这些复杂特征限制了我们对哮喘的理解和控制能力，并将继续使仅在单一尺度上处理反应的研究感到困惑。复杂的多尺度系统，就其本质而言，不能通过局限于几个参数的研究来理解。因此，本建议将遵循开发AHR多尺度实验和计算模型的创新和替代系统方法。我们将首先确定Ca2+振荡和肌动蛋白和肌球蛋白分子之间的过桥循环动力学如何决定asmc的力产生。随后，我们将确定这种力的产生是如何扭曲气道壁并导致整个肺部气道狭窄的。这将通过一个多学科研究小组的合作来实现，他们具有实验和数学专业知识，他们将把我们目前对不同细胞和组织水平的AHR的知识和理解整合到AHR的数学和计算模型中。该模型最初将包括符合气道收缩必需标准的现象，对AHR具有明确的重要性，并且可以通过实验进行迭代验证。在未来的研究中，将通过增加相关细节来完善该模型。该模型将用于分子、细胞和组织行为的具体预测，并提出关键的实验建议。结合理论和实验之间的广泛迭代，模型的子部分将被改进和验证，以确定连接连续过程或规模的基本参数。这项研究的结果将导致对哮喘和其他阻塞性肺疾病的基本细胞病理生理学和全肺反应之间的联系的更好理解，这将提高这些疾病的病因诊断和治疗效果。此外，由于AHR显然是一种复杂的症状，本研究将评估用系统生物学方法解决疾病的有效性。在美国，许多人患有哮喘，这是一种以气道过度收缩或气道超反应性（AHR）为特征的疾病。这种反应非常复杂，在分子水平上由空气中的过敏原或刺激引起，最终在器官水平上达到呼吸困难。本研究的目的是通过使用数学框架来指导和整合实验研究，阐明所涉及的每个过程的细节，从而发展对这一系列事件的理解。通过这种方法，可以识别AHR中的关键事件并针对其进行治疗干预。

DESCRIPTION (provided by applicant): Summary: Asthmatic lungs typically respond to inhaled allergens with exaggerated reductions in airway function. This phenomenon is termed airway hyper-responsiveness (AHR) and can be life threatening. AHR is not a simple reaction but is the culmination of multiple processes that manifest over a huge range of length and time scales. At one extreme, molecular signaling and interactions determine the force generated by airway smooth muscle cells (ASMCs). At the other extreme, contraction of the ASMCs is converted into a dynamic and complex constriction of branched airways that patients perceive by increased difficulty in breathing. Furthermore, asthma therapies are predominately pharmacological and operate at the molecular level, yet clinical outcomes are measured at the level of the whole lung. These two extremes are linked by numerous events operating at intermediate ranges of scale. These complex characteristics of AHR limit our understanding and ability to control asthma and will continue to confound research studies that only address responses at a single scale. Complex multi-scale systems cannot, by their very nature, be understood by studies limited to a few parameters. Consequently, this proposal will follow the innovative and alternative systems approach of developing a multi-scale experimental and computational model of AHR. We will initially determine how Ca2+ oscillations and the kinetics of cross-bridge cycling between actin and myosin molecules determine force production by ASMCs. Subsequently, we will determine how this force production distorts the airway wall and brings about airway narrowing throughout the lung. This will be achieved by the collaboration of a multidisciplinary group of investigators with experimental and mathematical expertise who will integrate our current knowledge and understanding of AHR at different cellular and tissue levels into a mathematical and computational model of AHR. The model will initially include phenomena that meet the criteria of being essential for airway contraction, of clear importance to AHR and experimentally accessible for iterative validation. In future studies, this model will be refined by the addition of relevant details. The model will be used to make specific predictions of molecular, cellular and tissue behavior and suggest critical experiments. In combination with extensive iteration between theory and experimentation, the sub-sections of the model will be refined and validated to identify the fundamental parameters that link the successive processes or scales. The results of this investigation will lead to an improved understanding of the link between the basic cellular pathophysiology and the whole lung response in asthma and other obstructive lung diseases This will improve the diagnosis of cause and effectiveness of treatment of these diseases. In addition, because AHR is clearly a complicated symptom, this investigation will evaluate the effectiveness of addressing disease with a systems biology approach. Many individuals in the USA suffer from asthma, a condition that is characterized by an exaggerated airway contraction or airway hyper-responsiveness (AHR). This response is extremely complicated being initiated at the molecular level by airborne allergens or stimuli and culminating at the organ level with difficulty in breathing. The objective of this research is to develop an understanding of this sequence of events by using a mathematical framework to guide and integrate experimental studies that elucidate the details of each process involved. With this approach, the key events in AHR can be identified and targeted for therapeutic intervention.