Molecular Imaging of the Lung Using Hyperpolarized Carbon-13 Compounds

描述（由申请人提供）：肺一度被认为是仅负责气体交换的代谢被动器官，但在过去几十年中已被证明在维持身体稳态方面发挥着各种关键作用。研究表明，其中一些稳态过程在肺部疾病中受到损害，并且肺部本身可能因暴露于其调节和失活途径的产物而受损。虽然成像方法的进步为肺部疾病的结构和功能表征及其在气体交换中的作用提供了新的方法，但能够提供有关维持体内平衡的这些代谢过程的分子和细胞途径信息的成像方法知之甚少。 该提案旨在开发针对肺的三种更快速和更好特征的代谢作用的特异性药物。 具体来说，这些包括调节肺组织和血浆中的糖酵解中间体、氨基酸水平和血管活性胺。 存在重要证据表明，每种代谢作用在阻塞性心脏病中都会发生改变。 疾病，或导致或加剧疾病的情况。 这项工作得益于使用高灵敏度核磁共振和成像来生产和研究超极化 13C 探针的通用技术的发展，以及最近的结果表明超极化状态如何保持比以前认为可能的更长时间。此外，这里选择的靶标非常适合超极化 13C 技术，因为它们是器官内发生的最快速的分子事件之一。 该提案的中心假设是：1）超极化探头，除了用于研究通气和气体交换的探头之外，还将提供一种灵敏的肺部实现稳态能力的探头，2）导出的指标可检测地依赖于与人类阻塞性疾病相关的疾病状态，3）这些探头可扩展到成像应用。 在解决这些假设时，我们提出以下具体目标：1）开发和测试用于研究糖酵解、氨基酸合成、炎症细胞代谢的分子探针，以及用于组织灌注测量的非代谢剂，2）测试上述每种探针在分离的灌注大鼠肺中的适用性，3）研究氧化还原状态在健康患病肺中的首要重要性，以及4）在大鼠和猪肺病模型中进行一系列代谢研究。许多肺部疾病，特别是慢性阻塞性肺病，其特征是全身能量代谢功能障碍，这可能部分是由于肺部无法维持糖酵解中间体的稳态所致。 我们相信，针对肺分子活性的超极化剂的开发和上述特定目标的实现将解决用于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。

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.