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：
7291449
负责人：
MICHAEL J. SANDERSON
金额：
$ 22.86万
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/7291449
关键词：
3-Dimensional Actins Address Aerosols Affect Affinity Agonist Airway Resistance Allergens American Asthma Behavior Biomedical Engineering Blood Vessels Boston Breathing Caliber Calmodulin Cell membrane Cell model Cellular biology Characteristics Chest Clinical Collaborations Comparative Study Complex Computer Simulation Condition Constriction procedure Contracts Coupled Coupling Cyclic AMP Cytoskeletal Proteins Cytoskeleton Data Deposition Development Diagnosis Dimensions Disease Dose Effectiveness Electronics Elements Ensure Environmental air flow Epithelial Epithelial Cells Equilibrium Evaluation Event Exhibits Extracellular Matrix Facility Construction Funding Category Fiber Foundations Frequencies Functional disorder Funding Future Gases Gel Generations Goals Grant Heterogeneity Human Image Inbred BALB C Mice Indiana Individual Inflammation Institutes International Investigation Isometric Exercise Journals Kinetics Knowledge Lasers Lead Length Life Link Location Lung Lung diseases Measurement Measures Mechanics Mediating Medical Medical center Methodology Methods MgADP Microscopy Modeling Molecular Mouse Strains Mus Muscle Contraction Myosin ATPase Myosin Regulatory Light Chains Nature Noble Gases Numbers Obstructive Lung Diseases Organ Organ Model Outcome Outcome Measure Patients Peer Review Penetration Pennsylvania Pharmaceutical Preparations Phase Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Photons Physiology Play Process Production Property Proteins Publishing Pump Range Rate Reaction Recommendation Regulation Relaxation Research Research Personnel Rho-associated kinase Role Ryanodine Receptor Calcium Release Channel Signal Transduction Site Slice Smooth Muscle Smooth Muscle Myocytes Smooth Muscle Myosins Societies Staging Stimulus Stretching Structural Models Structure Structure of parenchyma of lung Study models Symptoms System Systems Biology Takeda brand of pioglitazone hydrochloride Technology Testing Therapeutic Intervention Thick Time TimeLine Tissue Model Tissues Travel Treatment Effectiveness Trees Universities Validation Vermont Work airborne allergen airway epithelium airway hyperresponsiveness arteriole base day electric impedance extracellular improved innovation inositol-1,4,5-triphosphate receptor intercellular communication lung lobe medical schools member model development molecular modeling mouse Smc1l1 protein mouse Smc1l2 protein mouse model multi-scale modeling multidisciplinary research study respiratory smooth muscle response success symposium 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：哮喘肺通常对吸入过敏原做出反应，导致气道功能过度降低。这种现象称为气道高反应性 (AHR)，可能危及生命。 AHR 不是一个简单的反应，而是在大范围的长度和时间尺度上显现的多个过程的高潮。在一种极端情况下，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，ASMC 的收缩转化为分支气道的动态且复杂的收缩，患者通过呼吸困难的增加来感知。此外，哮喘治疗主要是药理治疗，并在分子水平上进行，但临床结果是在整个肺水平上测量的。这两个极端是由许多中等规模的事件联系在一起的。 AHR 的这些复杂特征限制了我们控制哮喘的理解和能力，并将继续混淆仅解决单一尺度反应的研究。复杂的多尺度系统就其本质而言，无法通过仅限于几个参数的研究来理解。因此，本提案将遵循开发 AHR 多尺度实验和计算模型的创新和替代系统方法。我们将首先确定 Ca2+ 振荡以及肌动蛋白和肌球蛋白分子之间的跨桥循环动力学如何决定 ASMC 产生的力。随后，我们将确定这种力的产生如何扭曲气道壁并导致整个肺部的气道变窄。这将通过具有实验和数学专业知识的多学科研究人员小组的合作来实现，他们将把我们当前对不同细胞和组织水平的 AHR 的知识和理解整合到 AHR 的数学和计算模型中。该模型最初将包括满足气道收缩必需标准的现象，对 AHR 具有明显重要性，并且可通过实验进行迭代验证。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、细胞和组织行为进行具体预测，并提出关键实验建议。结合理论和实验之间的广泛迭代，模型的子部分将被细化和验证，以确定连接连续过程或规模的基本参数。这项研究的结果将有助于更好地了解哮喘和其他阻塞性肺疾病的基本细胞病理生理学与整个肺部反应之间的联系，这将改善这些疾病的病因诊断和治疗效果。此外，由于 AHR 显然是一种复杂的症状，因此这项研究将评估通过系统生物学方法解决疾病的有效性。在美国，许多人患有哮喘，这种疾病的特征是气道过度收缩或气道高反应性 (AHR)。这种反应极其复杂，由空气中的过敏原或刺激在分子水平上引发，并在器官水平上达到顶峰，导致呼吸困难。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，阐明所涉及的每个过程的细节，从而加深对这一系列事件的理解。通过这种方法，可以识别 AHR 中的关键事件并有针对性地进行治疗干预。