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

气道高反应性的多尺度方法：从分子到器官

• 批准号: 8135440
• 负责人: Jason HT Bates
• 金额: $ 89.84万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135440
• 关键词: Accounting; Actins; Address; Aerosols; Affect; Agonist; Air; Allergic inflammation; Asthma; Behavior; Binding; Biomedical Research; Breathing; Bronchoconstriction; Caliber; Cells; Characteristics; Clinical; Collaborations; Communities; Complex; Computational algorithm; Computer Simulation; Contractile Proteins; Contracts; Data; Development; Dyspnea; Economic Inflation; Environmental air flow; Equilibrium; Event; Functional disorder; Generations; Goals; Human; ITPR1 gene; Individual; Inflammation; Inflammatory; Inositol; Investigation; Kinetics; Lead; Length; Life; Link; Lung; Lung diseases; Maintenance; Measurement; Measures; Mechanics; Mediating; Methods; Modeling; Molecular; Morphology; Mus; Muscle; Muscle Contraction; Myosin ATPase; Myosin Light Chain Kinase; Organ; Outcome; Patients; Physiological; Process; Production; Property; Protein Dephosphorylation; Public Health; Regulation; Research; Research Personnel; Respiratory physiology; Role; Ryanodine Receptors; Series; Signal Transduction; Simulate; Slice; Smooth Muscle Myocytes; Solutions; Stimulus; Stress; Stretching; Structure of parenchyma of lung; System; Testing; Therapeutic; Therapeutic Intervention; Thin Filament; Time; TimeLine; Tissue Model; Tissues; Translating; Trees; Work; airborne allergen; airway hyperresponsiveness; asthmatic patient; base; clinical phenotype; complex biological systems; computerized tools; constriction; electric impedance; human tissue; improved; intravenous injection; lung basal segment; lung volume; mathematical model; mechanical behavior; methacholine; model development; mouse model; multi-scale modeling; myosin phosphatase; particle; protein activation; protein expression; prototype; public health relevance; research study; respiratory smooth muscle; response; surfactant; theories

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. PUBLIC HEALTH RELEVANCE: Many individuals worldwide suffer from asthma, an inflammatory lung disease characterized by excessive constriction of the airways. This excessive constriction, termed airway hyperresponsiveness (AHR) can be life- threatening and is the result of an extremely complicated sequence of events initiated at the molecular level by airborne allergens or other stimuli, and culminating at the organ level with difficulty in breathing. The objective of this research is to understand the sequence of events leading to AHR by using a mathematical model to integrate data from experimental studies that by themselves can only elucidate the details of each step. With this multi-scale approach, we will be able to identify key events in AHR that may serve as targets for therapeutic intervention.

描述（由申请人提供）：哮喘患者对吸入刺激的反应是气道口径过度减小，这种现象称为气道高反应性（AHR）。 AHR 非常复杂，反映了在大范围的长度和时间尺度上表现的多个过程。在一种极端情况下，分子相互作用决定了气道平滑肌 (ASM) 产生的力。在另一个极端，气道树的许多分支在空间上分布的收缩会导致持续的呼吸困难。同样，传统的哮喘治疗是药理学的，在分子水平上发挥作用，而临床结果则根据整体肺功能进行评估。这些极端事件与在中等长度和时间范围内发生的众多事件联系在一起。因此，AHR 是一种新兴现象，全面理解它极具挑战性。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，即每项实验研究只能在非常有限的范围内解决生理机制。我们解决这个难题的方法是构建一个模块化的多尺度数学模型，链接和集成多个尺度的实验数据。该模型目前的表现是 5 位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，结合了肌动蛋白-肌球蛋白动力学的力产生、Ca2+动力学的力调节、力依赖性组织变形和气道收缩。虽然该模型展示了我们项目的可行性，并且最重要的是，建立了用于在广泛尺度上建模的计算算法，但它目前仅代表一个初始框架。因此，在本提案中，我们打算开发我们独特的多尺度肺部计算模型，使其可用于对支气管收缩进行现实的预测，从而使我们能够识别对 AHR 影响最大的病理生理机制。我们将在这个扩展模型中包括：1）在分子水平上，定期跨桥循环和闩锁状态期间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Ca2+信号传导机制，3）在组织水平上，收缩ASM和决定气道狭窄的相对粘弹性组织之间的力的详细平衡，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性肺中机械阻抗的变化。通过理论和实验之间的广泛迭代，模型的模块将被单独验证，以确定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。这将提高我们对哮喘细胞病理生理学与临床表型之间联系的理解。 公共卫生相关性：世界各地有许多人患有哮喘，这是一种以气道过度收缩为特征的炎症性肺部疾病。这种过度收缩，称为气道高反应性（AHR），可能会危及生命，是由空气中的过敏原或其他刺激物在分子水平上引发的极其复杂的一系列事件的结果，最终在器官水平上导致呼吸困难。这项研究的目的是通过使用数学模型整合来自实验研究的数据来了解导致 AHR 的事件顺序，而实验研究本身只能阐明每个步骤的细节。通过这种多尺度方法，我们将能够识别 AHR 中的关键事件，这些事件可以作为治疗干预的目标。