Assessment of lung function in small animals

小动物肺功能评估

• 批准号: 7266582
• 负责人: RAHIM R RIZI
• 金额: $ 39.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266582
• 关键词: Address; Air; Alveolar; Alveolar wall; Animal Model; Animals; Blood capillaries; Cell Death; Characteristics; Chronic; Classification; Clinical; Data; Deterioration; Diffusion; Disease; Disease Management; Disease Progression; Disease model; Early Diagnosis; Elastases; Endothelium; Environmental air flow; Equilibrium; Evolution; Exercise Tolerance; Exhalation; Exposure to; Functional disorder; Funding; Gases; Gold; Grant; Histology; Hour; Human; Hypoxia; Image; Inflammation; Inflammatory; Invasive; Investigation; Light; Lobar; Longitudinal Studies; Lung; Lung diseases; Magnetic Resonance Imaging; Magnetism; Measurement; Measures; Mediator of activation protein; Methods; Metric; Microscopic; Microspheres; Modeling; Modification; Molecular; Nature; Noble Gases; Oxygen measurement, partial pressure, arterial; Pancreatic Elastase; Pathogenesis; Pattern; Perfusion; Physiological; Plant Roots; Process; Protocols documentation; Pulmonary Emphysema; Pulmonary Hypertension; Pulmonary Ventilation; Pulmonary function tests; Pulmonology; Rattus; Reproducibility; Research; Research Personnel; Respiratory physiology; SU 5416; Smoking; Spin Labels; Sprague-Dawley Rats; Staging; Standards of Weights and Measures; Structure; Sum; Techniques; Tidal Volume; Time; Tissues; Today; Tracer; Uncertainty; Validation; Vascular Endothelial Growth Factors; Week; Whole Body Plethysmography; Work; angiogenesis; base; blood perfusion; capillary; cigarette smoking; cohort; density; design; drug discovery; human disease; in vivo; inhibitor/antagonist; insight; molecular modeling; normal aging; programs; repaired; response; theories

DESCRIPTION (provided by applicant): Non-invasive, regional assessment of lung function has the potential to markedly enhance early diagnosis and management of disease, to accelerate drug discovery and trials, and to provide fundamental insights into the root causes of disease. In this proposal, we aim to address a fundamental question of emphysema pathogenesis thorough a systematic study of lung function and structure using techniques developed over the first funding cycle. These techniques include measurements of pulmonary ventilation and perfusion, alveolar oxygen tension, and a sensitive measure of lung microstructure using hyperpolarized magnetic tracers, as well as several well-established methods in pulmonary medicine. The proposed research is designed specifically to corroborate or refute a molecular model of emphysema progression that is currently under widespread debate. Despite extensive investigation, it is still not clear which of the numerous and varied presentations of emphysema corresponds to the fundamental cause of the disease, or even if one principal cause can be identified. Nonetheless, a large body of current research suggests that altered expression of one or more mediators of angiogenesis may be the first step in the disease. This alteration degrades the capillary endothelium's ability to repair itself, resulting in cell death, reduced perfusion, and ultimately tissue destruction. Although in vivo imaging methods cannot replace the powerful molecular techniques in use today, they can provide a more complete picture of the action of disease or therapy on the body. In this study, we first demonstrate a comprehensive, self-consistent, and validated set of pulmonary measurements and evaluate sensitivity to disease. We then apply these measurements to three animal models of emphysema in order to evaluate time ordering and spatial correlation of the various aspects of pulmonary dysfunction. By comparing these measurements to testable predictions of the disease model, we hope to elucidate the first stages of this devastating disease.

描述(由申请人提供)：肺功能的非侵入性、区域性评估有可能显著提高疾病的早期诊断和管理，加快药物发现和试验，并提供对疾病根本原因的基本见解。在这项提案中，我们的目标是通过使用在第一个资金周期开发的技术对肺功能和结构进行系统研究来解决肺气肿发病机制的一个基本问题。这些技术包括测量肺通气量和灌注量、肺泡氧分压、使用超极化磁示踪剂灵敏地测量肺微结构，以及肺部医学中几种成熟的方法。这项拟议的研究专门旨在证实或驳斥目前正处于广泛辩论中的肺气肿进展的分子模型。尽管进行了广泛的调查，但仍不清楚肺气肿的众多不同表现中，哪一种与疾病的根本原因相对应，或者是否可以确定一个主要原因。尽管如此，目前的大量研究表明，血管生成的一个或多个介质的表达改变可能是疾病的第一步。这种改变降低了毛细血管内皮细胞自我修复的能力，导致细胞死亡，血流减少，最终导致组织破坏。虽然活体成像方法不能取代当今使用的强大的分子技术，但它们可以提供疾病或治疗对身体的作用的更完整的图景。在这项研究中，我们首先展示了一套全面的、自我协调的和经过验证的肺部测量方法，并评估了对疾病的敏感性。然后，我们将这些测量应用于三种肺气肿动物模型，以评估肺功能障碍各个方面的时间顺序和空间相关性。通过将这些测量与疾病模型的可测试预测进行比较，我们希望阐明这种毁灭性疾病的第一阶段。