Comprehensive Assessment of Pulmonary Disorders Using Polarized 13C Technology

使用偏光 13C 技术对肺部疾病进行综合评估

• 批准号: 8473071
• 负责人: RAHIM R RIZI
• 金额: $ 103.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473071
• 关键词: Accident and Emergency department; Affect; Alveolar; American; Animal Model; Area; Behavior; Betaine; Bicarbonates; Biochemical; Biological Markers; Biomedical Engineering; Bolus Infusion; Bronchiectasis; Carbon; Carbon Dioxide; Cardiovascular system; Cause of Death; Cells; Characteristics; Chemical Structure; Chemicals; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Complex; Cystic Fibrosis; Data; Dependence; Detection; Development; Diagnostic Equipment; Diffusion; Disease; Drug Formulations; Early Diagnosis; Effectiveness; Enhancers; Environment; Equilibrium; Equipment; Freezing; Frequencies; Gadolinium; Gases; Goals; Hospitalization; Image; Individual; Injection of therapeutic agent; Knowledge; Label; Life; Liquid substance; Lung; Lung diseases; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maps; Measurement; Measures; Medical; Medical Imaging; Metabolic; Metabolism; Methanol; Methods; Modeling; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Noise; Nuclear; Organ; Pathogenesis; Pathology; Pattern; Perfusion; Physiological; Physiology; Plasma Proteins; Positioning Attribute; Process; Production; Property; Protein Binding; Pulmonary Emphysema; Pulmonary Gas Exchange; Pyruvate; Recommendation; Relaxation; Research; Research Personnel; Respiratory System; Respiratory physiology; Role; Sample Size; Sampling; Signal Transduction; Spectrum Analysis; Staging; Study of magnetics; Techniques; Technology; Testing; Time; Tracer; Travel; United States; Visit; biological systems; clinical application; disability; experience; flexibility; gadolinium oxide; improved; in vitro Model; in vivo; instrument; intravenous administration; knowledge base; magnetic field; microwave electromagnetic radiation; mortality; novel; novel therapeutic intervention; pre-clinical; public health relevance; theories; tool; treatment strategy; uptake; working group

DESCRIPTION (provided by applicant): The goal of this Bioengineering Research Partnership is to develop new techniques for the comprehensive assessment of lung function by producing hyperpolarized tracer molecules (bicarbonate/CO2, betaine, cyclopropanedimethanol, and pyruvate) for MR imaging and spectroscopy of both normal and diseased lungs. We will use the method of dynamic nuclear polarization (DNP) to produce hyperpolarized 13C-labeled compounds proposed in this application. First, we will improve the signal-to-noise for hyperpolarized tracer imaging by building a polarizer that operates in a 5.0 T magnetic field. Second, we will determine the characteristics of 13C-bicarbonate, betaine, cyclopropanedimethanol, and [1-13C]pyruvate under conditions relevant to molecule freezing, hyperpolarization, dissolution, and transport. The management and understanding of these technical parameters is a prerequisite to successful in vivo studies and to obtaining high levels of polarization of the proposed molecules. Although the physical descriptions of the DNP process do not include significant influence from the chemical environment of the sample, the achievable polarization level represents a balance between spin-diffusion, polarization transfer, and relaxation. To this end, we will determine the optimal polarization conditions, including the specific formulation of each molecule and its concentration, the concentration of the radical, polarization enhancer (gadolinium complex), co-freezing agents and the optimal microwave frequency for DNP, all compared against polarization build-up time, T1 relaxation time and the plateau polarization level. Third, we will establish in vitro models of these hyperpolarized substrates and will characterize their NMR and biochemical properties in physiologically relevant environments. To determine the effectiveness of these molecules as hyperpolarized agents for the proposed study, it is not sufficient to show that the molecule can be highly polarized in a reasonable time-scale in the DNP apparatus. It is equally important to characterize the properties of the tracers as they travel through the circulatory system towards the lungs. Forth, we will develop a technique for pH mapping of the lung through measurement of the 13C-bicarbonate/13CO2 balance after intravenous administration of 13C-bicarbonate, as well as assessing exchange of 13CO2 from the pulmonary vasculature to the alveolar space through measurement of the CO2/bicarbonate apparent T1. pH is a key parameter in most pathologies and mapping of this quantity has already been demonstrated through localized measurement of the pH-dependent bicarbonate/CO2 balance. Finally we will study pH, gas exchange and metabolism in an animal model of COPD with hyperpolarized 13C-bicarbonate and 13C-pyruvate. Assessment of lung function and pathology remains a clinical problem. We will test the application of methods developed above to a model of lung disease (COPD), and refine qualitative measures of metabolism and perfusion developed earlier. We will seek patterns characteristic to the diseased subject and, where possible, compare them to established methods of measuring pH, perfusion, gas exchange and metabolism. Keywords: Dynamic Nuclear Polarization, Hyperpolarized Carbon-13 MR Imaging, Lung Metabolism, pH Measurements, Gas Exchange.

描述（由申请人提供）：该生物工程研究合作伙伴关系的目标是开发用于综合评估肺功能的新技术，方法是生产超极化示踪分子（碳酸氢盐/二氧化碳、甜菜碱、环丙二甲醇和丙酮酸盐），用于正常和患病肺部的 MR 成像和光谱学。我们将使用动态核极化（DNP）方法来生产本申请中提出的超极化13C标记化合物。首先，我们将通过构建在 5.0 T 磁场中工作的偏振器来提高超极化示踪成像的信噪比。其次，我们将确定 13C-碳酸氢盐、甜菜碱、环丙烷二甲醇和 [1-13C]丙酮酸盐在分子冷冻、超极化、溶解和运输相关条件下的特性。对这些技术参数的管理和理解是成功体内研究和获得所提议分子的高水平极化的先决条件。尽管 DNP 过程的物理描述不包括样品化学环境的显着影响，但可实现的极化水平代表了自旋扩散、极化转移和弛豫之间的平衡。为此，我们将确定最佳的极化条件，包括每个分子的具体配方及其浓度、自由基的浓度、极化增强剂（钆络合物）、共冷冻剂和DNP的最佳微波频率，所有这些都与极化建立时间、T1弛豫时间和平台极化水平进行比较。第三，我们将建立这些超极化底物的体外模型，并在生理相关环境中表征它们的核磁共振和生化特性。为了确定这些分子作为所提出的研究的超极化剂的有效性，仅仅证明分子可以在 DNP 装置中在合理的时间范围内高度极化是不够的。当示踪剂通过循环系统流向肺部时，表征示踪剂的特性也同样重要。第四，我们将开发一种通过静脉注射 13C-碳酸氢盐后测量 13C-碳酸氢盐/13CO2 平衡来绘制肺部 pH 值的技术，以及通过测量 CO2/碳酸氢盐表观 T1 来评估 13CO2 从肺血管系统到肺泡腔的交换。 pH 值是大多数病理学中的关键参数，并且该量的绘图已通过 pH 依赖性碳酸氢盐/二氧化碳平衡的局部测量得到证明。最后，我们将使用超极化 13C-碳酸氢盐和 13C-丙酮酸盐研究 COPD 动物模型中的 pH、气体交换和代谢。肺功能和病理学的评估仍然是一个临床问题。我们将测试上述开发的方法在肺部疾病（COPD）模型中的应用，并完善先前开发的代谢和灌注的定性测量。我们将寻找患病受试者的特征模式，并在可能的情况下将其与测量 pH、灌注、气体交换和代谢的既定方法进行比较。关键词：动态核极化、超极化碳 13 MR 成像、肺代谢、pH 测量、气体交换。