A multi-scale approach to airway hyperresponsiveness: from molecule to organ

描述(由申请人提供)：哮喘患者对吸入刺激的反应是呼吸道口径过度缩小，这种现象被称为呼吸道高反应性(AHR)。AHR非常复杂，反映了在大范围的长度和时间范围内表现出来的多个过程。在一种极端情况下，分子相互作用决定了由呼吸道平滑肌(ASM)产生的力。在另一个极端，气道树的许多分支在空间上的收缩导致持续的呼吸困难。同样，传统的哮喘治疗是药理学的，在分子水平上运作，而临床结果是根据全球肺功能来评估的。这些极端是由许多事件联系在一起的，这些事件在长度和时间的中间尺度上运行。因此，AHR是一种紧急现象，对其整体理解是极具挑战性的。这反过来又限制了我们对哮喘的理解，并混淆了对实验研究的解释，即每项研究只能在非常有限的范围内解决生理机制。我们对这一难题的解决方案是构建一个模块化的多尺度数学模型，该模型连接和集成来自多个尺度的实验数据。这一模型的当前表现是5名具有互补实验和数学专业知识的研究人员之间多学科合作的结果，包括肌动蛋白-肌球蛋白动力学产生的力、钙动力学调节的力、依赖力的组织变形和气道收缩。虽然这个模型证明了我们项目的可行性，最重要的是，它建立了在广泛范围内建模的计算算法，但它目前只代表一个初始框架。因此，在这项提案中，我们打算开发我们独特的肺多尺度计算模型，以使其能够用于对支气管收缩做出现实的预测，从而使我们能够识别对AHR有最大影响的病理生理机制。我们将在这个扩展的模型中包括：1)在分子水平上，在常规跨桥循环和闩锁状态下，收缩蛋白的动力学及其对力产生的贡献；2)在细胞水平上，调节ASM力产生的钙信号机制；3)在组织水平上，收缩ASM和相对的粘弹性组织之间的力量的详细平衡决定了气道狭窄；以及4)在器官水平上，ASM收缩动力学的地形分布决定了正常和高反应肺的机械阻抗的变化。通过理论和实验之间的广泛迭代，将对模型的各个模块进行单独验证，以确定在连续尺度之间联系的关键参数。然后，该模型将用于对分子、细胞和组织行为进行可测试的预测。这将提高我们对细胞病理生理学和哮喘临床表型之间的联系的理解。

DESCRIPTION (provided by applicant): Asthmatic patients respond to inhaled stimuli with an excessive reduction in airway caliber, a phenomenon known as airway hyperresponsiveness (AHR). AHR is highly complex and reflects multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM). At the other extreme, the spatially distributed constriction of the many branches of the airway tree lead to persistent difficulties in breathing. Similarly, conventional asthma therapies are pharmacological and operate at the molecular level, while clinical outcomes are evaluated in terms of global lung function. These extremes are linked by numerous events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that is extremely challenging to understand in its entirety. This in turn limits our understanding of asthma and confounds the interpretation of experimental studies that each can address physiological mechanisms over only a very limited range of scales. Our solution to this conundrum has been to construct a modular multi-scale mathematical model that links and integrates experimental data from multiple scales. The current manifestation of this model, which is the result of a multi-disciplinary collaboration between 5 investigators with complementary experimental and mathematical expertise, incorporates force production by actin-myosin dynamics, force regulation by Ca2+ dynamics, force-dependent tissue deformation, and airway constriction. While this model demonstrates feasibility for our project and, most importantly, establishes computational algorithms for modeling over a wide range of scales, it currently represents only an initial frame-work. Consequently, in this proposal, we intend to develop our unique multi-scale computational model of the lung to the point where it can be used to make realistic predictions of bronchoconstriction, thereby allowing us to identify those pathophysiologic mechanisms having the greatest impact on AHR. We will include in this extended model: 1) at the molecular level, the kinetics of the contractile proteins during regular cross-bridge cycling and during the latch-state and their contributions to force production, 2) at the cellular level, the Ca2+ signaling mechanisms that regulate ASM force production, 3) at the tissue level, the detailed balance of forces between contracting ASM and the opposing viscoelastic tissue that determine airway narrowing, and 4) at the organ level, the topographic distribution of ASM contraction dynamics that determine changes in mechanical impedance in the normal and hyperresponsive lung. By extensive iteration between theory and experimentation, the modules of the model will be individually validated to identify the key parameters that link between successive scales. The model will then be used to make testable predictions of molecular, cellular and tissue behavior. This will improve our understanding of the link between cellular pathophysiology and the clinical phenotype in asthma.