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

基本信息

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
项目类别：
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

项目摘要

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）：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/CO2、甜菜碱、环丙二甲醇和丙酮酸盐），用于 MR 成像和光谱学正常和患病的肺。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）、共冻剂以及DNP的最佳微波频率，所有这些都进行比较针对极化建立时间、T1 弛豫时间和平台极化水平。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 值图的技术，以及通过测量 13C-碳酸氢盐从肺血管系统到肺泡腔的 13CO2 交换来评估CO2/碳酸氢盐表观 T1。 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。公共卫生相关性：超极化碳 13 MR 成像和光谱学有可能以前所未有的灵敏度揭示慢性阻塞性肺疾病引起的肺部代谢和生理变化。重要的临床应用包括肺气肿和囊性纤维化的早期诊断，以及扩展该领域的知识库以发现新的治疗干预措施。