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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

基本信息

批准号：
8502325
负责人：
Jason HT Bates
金额：
$ 85.53万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8502325
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

项目摘要

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.

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。

项目成果

期刊论文数量（32）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phenotype, endotype and patient-specific computational modelling for optimal treatment design in asthma.

表型、内型和患者特异性计算模型，用于哮喘的最佳治疗设计。

DOI：
10.1016/j.ddmod.2014.02.007
发表时间：
2015
期刊：
Drug discovery today. Disease models
影响因子：
0
作者：
Donovan,GrahamM;Tawhai,MerrynH
通讯作者：
Tawhai,MerrynH

CD4+ T cells enhance the unloaded shortening velocity of airway smooth muscle by altering the contractile protein expression.

CD4 T 细胞通过改变收缩蛋白的表达来增强气道平滑肌的无负荷缩短速度。

DOI：
10.1113/jphysiol.2014.270843
发表时间：
2014
期刊：
The Journal of physiology
影响因子：
0
作者：
Matusovsky,OlegS;Nakada,EmilyM;Kachmar,Linda;Fixman,ElizabethD;Lauzon,Anne-Marie
通讯作者：
Lauzon,Anne-Marie

Peripheral Airway Smooth Muscle, but Not the Trachealis, Is Hypercontractile in an Equine Model of Asthma.

在马哮喘模型中，周围气道平滑肌（而非气管肌）收缩过度。

DOI：
10.1165/rcmb.2015-0180oc
发表时间：
2016
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
Matusovsky,OlegS;Kachmar,Linda;Ijpma,Gijs;Bates,Genevieve;Zitouni,Nedjma;Benedetti,Andrea;Lavoie,Jean-Pierre;Lauzon,Anne-Marie
通讯作者：
Lauzon,Anne-Marie

The importance of synergy between deep inspirations and fluidization in reversing airway closure.

深吸气和流化之间的协同作用在逆转气道关闭中的重要性。