Airway Hyper-responsiveness: from molecule to organ

总结：哮喘肺通常对吸入性过敏原有反应， 气道功能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，而是多个过程的顶点，这些过程在很大范围内表现出来。 长度和时间尺度。在一个极端，分子信号传导和相互作用决定了 气道平滑肌细胞（ASMCs）。在另一个极端，ASMC的收缩被转化为 支气管的动态和复杂的收缩，患者通过增加的困难感觉到， 呼吸了此外，哮喘治疗主要是药理学的，并且在分子水平上起作用。 然而，临床结果是在整个肺的水平上测量的。这两个极端是由 在中等规模范围内运作的许多事件。AHR的这些复杂特征限制了我们的研究。 控制哮喘的理解和能力，并将继续混淆研究，只解决 在单一尺度下的反应。复杂的多尺度系统就其本质而言， 研究仅限于几个参数。因此，本提案将遵循创新和备选方案， 系统的方法开发一个多尺度的实验和计算模型的AHR。我们将 初步确定肌动蛋白和肌球蛋白之间的钙振荡和跨桥循环动力学 分子决定ASMCs的力产生。随后，我们将确定这支部队是如何生产的 使气道壁变形并导致整个肺的气道变窄。 这将通过一个多学科研究小组与实验室的合作来实现。 和数学专业知识，他们将整合我们目前的知识和对AHR的理解， 细胞和组织水平转化为AHR的数学和计算模型。该模型最初将包括 符合气道收缩所必需的标准的现象，对AHR具有明确的重要性， 实验上可用于迭代验证。在未来的研究中，将通过添加以下内容来完善该模型： 相关细节。该模型将用于对分子、细胞和组织行为进行具体预测 并建议进行批判性实验。结合理论和实验之间的广泛迭代， 将对模型的各个子部分进行细化和验证，以确定将 连续的过程或尺度。这项调查的结果将有助于更好地了解 哮喘和其他阻塞性疾病的基本细胞病理生理学与整个肺反应之间的联系 这将提高对这些疾病的病因诊断和治疗效果。在 此外，由于AHR显然是一种复杂的症状，本研究将评估 用系统生物学的方法解决疾病。

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.