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: 8281537
• 负责人: RAHIM R RIZI
• 金额: $ 110.66万
• 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/8281537
• 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; 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. PUBLIC HEALTH RELEVANCE: Hyperpolarized carbon-13 MR imaging and spectroscopy has the potential to reveal metabolic and physiological alterations in lung induced by chronic obstructive pulmonary diseases with an unprecedented sensitivity. Important clinical applications include early diagnosis of emphysema and cystic fibrosis and to expand the knowledge base in this area for discovering new therapeutic interventions.

描述（由申请人提供）：这种生物工程研究伙伴关系的目的是通过产生超极化的示踪剂分子（碳酸氢盐/二氧化碳，BETAINE，betaine，betaine，betaine，celloparopanedimethanol和pyruvate）来开发肺功能全面评估的新技术。我们将使用动态核极化方法（DNP）产生本应用中提出的超极化的13C标记化合物。首先，我们将通过在5.0 t磁场中构建偏振器来改善超极化示踪剂成像的信噪。其次，我们将在与分子冷冻，超极化，溶解和运输的条件下确定13C双碳酸盐，甜菜碱，环丙基甲醇和[1-13C]丙酮酸的特征。对这些技术参数的管理和理解是成功进行体内研究并获得高水平的分子极化的先决条件。尽管DNP过程的物理描述不包括样品的化学环境的重大影响，但可实现的极化水平代表了自旋扩散，极化转移和放松之间的平衡。为此，我们将确定最佳极化条件，包括每个分子的特定配方及其浓度，自由基，极化增强子（Gadolinium Complex）的浓度，偶联剂和DNP的最佳微波频率，所有相对于偏光时间，T1松弛时间和高原极化水平相比，所有分子的最佳微波炉频率均相比。第三，我们将建立这些超极化底物的体外模型，并在生理相关的环境中表征其NMR和生化特性。为了确定这些分子作为拟议研究的超极化剂的有效性，不足以证明该分子可以在DNP设备中合理的时间尺度上高度极化。表征示踪剂在循环系统向肺部传播时的性质同样重要。第四，我们将通过测量13c-碳酸氢盐给药后通过测量13C-碳酸氢盐/13CO2平衡来开发一种用于肺部pH映射的技术，并通过测量CO2/Bicaranate Samey T1的测量来评估从肺脉管系统到肺泡空间的13CO2交换。 pH是大多数病理学中的关键参数，该量的映射已经通过局部测量pH依赖性碳酸氢盐/CO2平衡来证明。最后，我们将研究具有超极化13C-双碳酸盐和13C-丙酮酸的COPD动物模型中的pH，气体交换和代谢。肺功能和病理的评估仍然是一个临床问题。我们将测试上面开发的方法对肺部疾病模型（COPD）的应用，以及早期开发的代谢和灌注的定性测量方法。我们将寻求以患病受试者为特征的模式，并在可能的情况下将它们与既定的pH，灌注，气体交换和代谢的既定方法进行比较。关键字：动态核极化，超极化碳13 MR成像，肺代谢，pH测量，气体交换。 公共卫生相关性：超极化碳13 MR成像和光谱法具有揭示慢性阻塞性肺部疾病诱导的具有前所未有的敏感性的肺的代谢和生理改变。重要的临床应用包括肺气肿和囊性纤维化的早期诊断，并扩大该领域的知识库，以发现新的治疗干预措施。