Molecular Imaging of the Lung Using Hyperpolarized Carbon-13 Compounds

描述(申请人提供)：肺曾经被认为是代谢被动的器官，只负责气体交换，在过去的几十年里，已经显示出在维持身体动态平衡方面发挥着各种关键作用。研究表明，其中一些动态平衡过程在肺部疾病中受到损害，肺本身可能因暴露于其调节和失活途径的产物而受到损害。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，但能够提供维持体内平衡的这些代谢过程的分子和细胞途径的成像方法还不太了解和开发。 这项提议寻求开发专用于肺的三种更快速和更具特征的代谢作用的药物。具体地说，这些包括调节肺组织和血浆中的糖酵素中间体、氨基酸水平和血管活性胺。有重要证据表明，在梗阻性疾病中，每种代谢作用都会发生改变 疾病，或在导致或加剧疾病的情况下。这项工作得到了利用高灵敏度核磁共振和成像来生产和研究超极化13C探针的一般技术的发展，以及最近的结果，这些结果表明超极化状态可以保持比之前认为的更长的时间。此外，这里选择的靶非常适合超极化13C技术，因为它们是器官内发生的最快的分子事件之一。 这一提议的中心假设是：1)超极化探头，除了用于研究呼吸和气体交换的探头外，将提供肺实现动态平衡的能力的灵敏探头，2)导出的指标可检测到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。为了解决这些假设，我们提出了以下具体目标：1)开发和测试用于研究糖酵解、氨基酸合成、炎性细胞代谢和用于组织灌流测量的非代谢药物的分子探针，2)测试上述每个探针在分离的、灌流的大鼠肺中的适用性，3)研究氧化还原状态在健康病变肺中的首要重要性，以及4)在大鼠和猪的肺部疾病模型上进行一系列代谢研究。许多肺部疾病，尤其是COPD，以全身能量代谢紊乱为特征，这可能部分是由于肺未能维持糖酵解中间产物的动态平衡。 我们相信，以肺分子活动为靶点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在研究肺内稳态功能及其与疾病状态的关系方面的不足。

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.