Airway hyper-responsiveness: from molecule to organ

描述(由申请人提供)：摘要：哮喘肺通常对吸入变应原有明显的呼吸道功能减退。这种现象被称为呼吸道高反应性(AHR)，可能危及生命。AHR不是一个简单的反应，而是在一个巨大的长度和时间范围内表现出来的多个过程的结果。在一个极端，分子信号和相互作用决定了由呼吸道平滑肌细胞(ASMC)产生的力。在另一种极端情况下，ASMCs的收缩转化为动态而复杂的分支呼吸道收缩，患者感觉到呼吸困难增加。此外，哮喘的治疗主要是药理学的，并在分子水平上运作，但临床结果是在整个肺的水平上衡量的。这两个极端是由许多在中等规模范围内发生的事件联系在一起的。AHR的这些复杂特征限制了我们对控制哮喘的理解和能力，并将继续扰乱仅针对单一级别反应的研究研究。复杂的多尺度系统，就其本质而言，不能通过仅限于几个参数的研究来理解。因此，这项提议将遵循创新和替代系统方法，开发一个多尺度的AHR实验和计算模型。我们将初步确定钙离子振荡和肌动蛋白和肌球蛋白分子之间跨桥循环的动力学如何决定ASMCs的力产生。随后，我们将确定这种力的产生如何扭曲气道壁，并导致整个肺的气道狭窄。这将通过一个具有实验和数学专业知识的多学科研究人员小组的合作实现，他们将把我们目前在不同细胞和组织水平上对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对呼吸道收缩至关重要的标准的现象，对AHR具有明显的重要性，并可通过实验进行迭代验证。在未来的研究中，这一模型将通过添加相关细节进行细化。该模型将用于对分子、细胞和组织行为进行具体预测，并建议进行关键实验。结合理论和实验之间的广泛迭代，将改进和验证模型的子部分，以确定连接连续过程或规模的基本参数。本研究的结果将有助于加深对哮喘和其他阻塞性肺疾病基本细胞病理生理学和全肺反应之间联系的了解，从而提高对这些疾病的病因和治疗效果的诊断。此外，由于AHR显然是一种复杂的症状，这项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，这种疾病的特征是呼吸道过度收缩或气道高反应性(AHR)。这种反应是极其复杂的，由空气传播的过敏原或刺激在分子水平上启动，并在器官水平上达到高潮，导致呼吸困难。这项研究的目的是通过使用一个数学框架来指导和整合阐明每个过程细节的实验研究，从而加深对这一系列事件的理解。通过这种方法，可以识别AHR中的关键事件并将其作为治疗干预的目标。

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.