Airway Hyper-responsiveness: from molecule to organ

气道高反应性：从分子到器官

基本信息

批准号：
7624173
负责人：
MICHAEL J. SANDERSON
金额：
$ 23.83万
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：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7624173
关键词：
3-Dimensional Actins Address Affinity Agonist Airway Resistance Allergens Asthma Behavior Blood Vessels Breathing Caliber Cell membrane Cell model Characteristics Clinical Collaborations Complex Computer Simulation Contracts Cyclic AMP Data Diagnosis Dimensions Disease Dose Effectiveness Event Exhibits Fiber Frequencies Functional disorder Future Generations Goals Heterogeneity Image Inbred BALB C Mice Individual Investigation Isometric Exercise Kinetics Knowledge Lead Length Life Link Location Lung Lung diseases MYLK gene Measurement Mechanics Mediating MgADP Modeling Molecular Molecular Models Mouse Strains Mus Muscle Contraction Myosin ATPase Nature Obstructive Lung Diseases Organ Outcome Outcome Measure Patients Process Production Pump Reaction Relaxation Research Research Personnel Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Signal Transduction Site Smooth Muscle Smooth Muscle Myocytes Smooth Muscle Myosins Stimulus Structure Structure of parenchyma of lung Study models Symptoms System Systems Biology Takeda brand of pioglitazone hydrochloride Testing Therapeutic Intervention Time Tissue Model Tissues Treatment Effectiveness Trees Validation airborne allergen airway epithelium airway hyperresponsiveness constriction electric impedance extracellular improved innovation intercellular communication meetings molecular modeling mouse model multi-scale modeling multidisciplinary receptor research study respiratory smooth muscle response theories

项目摘要

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.

描述（由申请人提供）：摘要：哮喘肺通常会响应吸入过敏原，而气道功能夸大。这种现象被称为气道高反应性（AHR），可能会威胁生命。 AHR并不是一个简单的反应，而是在大量长度和时间尺度上表现出的多个过程的顶点。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（ASMC）产生的力。在另一个极端情况下，ASMC的收缩被转化为分支气道的动态且复杂的收缩，患者通过增加呼吸困难而感知的。此外，哮喘疗法主要是药理学，并且在分子水平上起作用，但在整个肺部的水平上测量了临床结局。这两个极端与在规模中间范围内运行的许多事件联系在一起。 AHR的这些复杂特征限制了我们控制哮喘的理解和能力，并将继续混淆仅针对单一量表的反应的研究。复杂的多尺度系统的性质不能通过仅限于一些参数的研究来理解。因此，该建议将遵循开发AHR多规模实验和计算模型的创新和替代系统方法。我们最初将确定肌动蛋白和肌球蛋白分子之间的CA2+振荡和跨桥循环的动力学如何确定ASMC的力产生。随后，我们将确定这种力量产生如何扭曲气道墙，并使气道在整个肺部变窄。这将是通过与实验和数学专业知识的多学科研究者的合作来实现的，他们将在不同的细胞和组织水平上将我们当前对AHR的知识和对AHR的了解整合到AHR的数学和计算模型中。该模型最初将包括符合气道收缩至关重要的标准的现象，对AHR至关重要，并且可以在迭代验证方面访问实验。在未来的研究中，该模型将通过添加相关细节来完善。该模型将用于对分子，细胞和组织行为的特定预测，并提出关键实验。结合理论和实验之间的广泛迭代，将对模型的子段进行完善和验证，以确定将连续过程或量表联系起来的基本参数。这项研究的结果将导致人们对哮喘和其他阻塞性肺部疾病的基本细胞病理生理学与整个肺部反应之间的联系有了深入的了解，这将改善对这些疾病的病因和有效性的诊断。此外，由于AHR显然是一个复杂的症状，因此该研究将评估通过系统生物学方法解决疾病的有效性。美国许多人患有哮喘，这种疾病的特征是气道收缩或气道高反应性（AHR）。这种反应是通过空气传播或刺激在分子水平上引发的，并在器官水平上以难度在器官水平上引发这种反应。这项研究的目的是通过使用数学框架来指导和整合实验研究，以阐明涉及每个过程的细节，从而发展对这一事件序列的理解。通过这种方法，可以将AHR中的关键事件识别为治疗干预。