Molecular Imaging of the Lung Using Hyperpolarized Carbon-13 Compounds

描述（由申请人提供）：肺曾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显示在维持体内稳态方面发挥各种关键作用。研究表明，这些稳态过程中的一些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已经使得能够采用新的方法来表征肺部疾病的结构和功能以及它们在气体交换中的作用，但是能够提供关于维持体内平衡的这些代谢过程的分子和细胞途径的信息的成像方法较少被理解和开发。 该提案旨在开发针对肺的三种更快速和更好表征的代谢作用的药物。 具体而言，这些包括调节肺组织和血浆中的糖酸中间体、氨基酸水平和血管活性胺。 有重要证据表明，在阻塞性疾病中，每种代谢作用都发生了改变。 疾病，或导致或加剧疾病的条件。 这项工作得到了一般技术的发展的帮助，以生产和研究超极化13 C探针使用高灵敏度NMR和成像，以及最近的结果，显示如何超极化状态可以保持更长的时间比以前认为可能的。此外，这里选择的靶点非常适合超极化13 C技术，因为它们是器官内发生的最快速的分子事件之一。 该提议的中心假设是：1）超极化探头，除了用于研究通气和气体交换的那些探头之外，将提供肺实现体内平衡的能力的灵敏探头，2）导出的度量可检测地依赖于与人类阻塞性疾病相关的疾病状态，以及3）这些探头可扩展到成像应用。 在处理这些假设时，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、炎性细胞代谢的分子探针，以及用于组织灌注测量的非代谢试剂，2）测试每种上述探针在分离的灌注大鼠肺中的适用性，3）研究健康患病肺中氧化还原状态的首要重要性，以及4）在肺疾病的大鼠和猪模型中进行一系列代谢研究。许多肺部疾病，特别是COPD的特征在于全身能量代谢功能障碍，这可能部分是由于肺无法维持糖酵解中间体的稳态。 我们相信，针对肺分子活性的超极化药物的开发和上述特定目标的实现将解决现有技术的缺点，用于研究肺稳态功能及其与疾病状态的关联。

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.