Molecular Imaging of the Lung Using Hyperpolarized Carbon-13 Compounds

使用超极化碳 13 化合物对肺部进行分子成像

• 批准号: 8417368
• 负责人: RAHIM R RIZI
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417368
• 关键词: 5-Hydroxytryptophan; Acetoacetates; Address; Affect; Amines; Amino Acids; Animals; Area; Betaine; Blood; Blood Circulation; Butyrates; Carbon; Cells; Chronic Obstructive Airway Disease; Comorbidity; Cytoplasm; Development; Diagnosis; Disease; Disease Progression; Energy Metabolism; Environmental air flow; Equilibrium; Event; Exposure to; Failure; Family suidae; Future; Gases; Glutamate-Ammonia Ligase; Glutamates; Glutamine; Glycolysis; Goals; Health; Heart; Histological Techniques; Homeostasis; Hormonal; Hormones; Human; Image; Inflammatory; Ischemia; Lead; Lung; Lung Inflammation; Lung diseases; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolism; Methods; Metric; Mitochondria; Modeling; Modification; Molecular; Molecular Probes; New Agents; Obstructive Lung Diseases; Organ; Oxidation-Reduction; Pathogenesis; Pathway interactions; Perfusion; Plasma; Positron-Emission Tomography; Process; Pyruvate; Rattus; Reactive Oxygen Species; Regulation; Respiratory physiology; Role; Series; Serotonin; Signal Transduction; Source; Specificity; Staging; Structure of parenchyma of lung; Surface; Techniques; Technology; Testing; Tissues; Translations; Validation; Vascular blood supply; Work; abstracting; analog; body system; disease diagnosis; imaging modality; insight; metabolic abnormality assessment; molecular imaging; novel strategies; phthalates; uptake

DESCRIPTION (provided by applicant): Once considered a metabolically passive organ responsible only for gas exchange, the lung has been shown to perform a variety of critical roles in maintaining body homeostasis in the last few decades. Studies show that some of these homeostatic processes are compromised in lung disease and the lung itself may be damaged by exposure to the products of its regulation and deactivation pathways. While advances in imaging methods have enabled new approaches for structural and functional characterization of pulmonary disorders and their role in gas exchange, imaging methods capable of providing information about the molecular and cellular pathways of these metabolic processes that maintain homeostasis are less understood and developed. This proposal seeks to develop agents specific to three of the more rapid and better-characterized metabolic roles of the lung. Specifically, these include the regulation of glycolytc intermediates, amino acid levels, and vasoactive amines in both the lung tissue and the blood plasma. Significant evidence exists that each metabolic role is modified in obstructive disease, or in conditions that lead to or exacerbate the disease. The work is aided by the development of general techniques to produce and study hyperpolarized 13C probes using high-sensitivity NMR and imaging, and recent results which show how the hyperpolarized state may be maintained for a longer period than was previously thought possible. Furthermore, the targets chosen here are well suited to hyperpolarized 13C technology because they are among the most rapid molecular events that take place within the organ. The central hypotheses of this proposal are that 1) hyperpolarized probes, beyond those in use for studying ventilation and gas exchange, will provide a sensitive probe of the ability of the lung to achieve homeostasis, 2) derived metrics are detectably dependent on disease state relevant to human obstructive disease, and 3) these probes are extensible to imaging applications. In addressing these hypotheses we propose the following specific aims: 1) Development and testing of molecular probes for studying glycolysis, amino acid synthesis, metabolism of inflammatory cells, and non-metabolitzed agents for tissue perfusion measurement, 2) Testing the applicability of each of the aforementioned probes in the isolated, perfused rat lung, 3) Studying the primary importance of redox states in healthy diseased lung, and 4) Performing a series of metabolic studies in rat and pig models of lung disease. Many pulmonary disorders and in particular COPD are characterized by dysfunctional whole-body energy metabolism, which may in part result from the lung's failure to maintain homeostasis of glycolytic intermediates. We believe that the development of hyperpolarized agents targeted to lung molecular activity and accomplishment of the above specific aims will address the shortcomings of existing techniques for studying lung homeostatic functions and their associations with disease state. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop noninvasive metabolic probes for assessment of lung disease and to develop lung redox imaging using hyperpolarized 13C technology. Completion of the specific aims will provide insights about disease pathogenesis and facilitate new agents for obstructive disease diagnosis and staging. (End of Abstract)

描述（由申请人提供）：一旦被视为仅负责气体交换的代谢被动器官，肺部已被证明在过去几十年中可以在维持身体体内平衡方面发挥各种关键作用。研究表明，其中一些体内稳态过程在肺部疾病中受到损害，肺本身可能会因其调节和失活途径的产物而受损。虽然成像方法的进步已使肺部疾病的结构和功能表征的新方法及其在气体交换中的作用，但能够提供有关这些代谢稳态的分子和细胞途径的信息的成像方法，这些方法较少理解和开发。 该提案旨在开发特定于肺部更快，更敏化的代谢作用的特定的药物。 具体而言，这些包括调节肺组织和血浆中的糖溶剂中间体，氨基酸水平和血管活性胺。 存在大量证据表明，每个代谢作用在阻塞性中都经过改变 疾病，或在导致或加剧疾病的情况下。 这项工作得到了一般技术的发展，该技术使用高敏性NMR和成像来生产和研究超极化的13C探针，最近的结果表明，如何在比以前认为的更长的时间内保持超极化状态更长。此外，此处选择的目标非常适合超极化13C技术，因为它们是器官内发生的最快的分子事件之一。 该提案的中心假设是：1）超极化探针除了用于研究通风和气体交换的探针外，还将提供对肺有能力达到稳态的能力的敏感探针，2）衍生的指标可检测到与人类阻塞性疾病相关的疾病状态，以及3）这些探针对成像的应用是扩展的。 在解决这些假设时，我们提出了以下特定目的：1）研究和测试分子探针研究糖酵解，氨基酸合成，炎症细胞的代谢，非代谢剂的组织灌注测量，2）在隔离探针中的适用性，以隔离率的适用性，是在隔离型的适用性中，该爆炸率是北次雷管的适用性，患病的肺，4）在大鼠和肺部疾病的猪模型中进行一系列代谢研究。许多肺部疾病，尤其是COPD的特征是功能失调的全身能量代谢，这可能部分是由于肺无法维持糖酵解中间体的稳态。 我们认为，针对肺部分子活性的超极化剂的发展和上述特定目标的完成将解决研究肺稳态功能及其与疾病状态的关联的现有技术的缺点。 公共卫生相关性：该项目的目的是开发无创的代谢探针，以评估肺部疾病并使用超极化13C技术开发肺氧化还原成像。具体目标的完成将提供有关疾病发病机理的见解，并促进新的药物进行阻塞性疾病诊断和分期。 （抽象的结尾）