Imaging phenotypes in copper metabolism disease in mice

说明(申请人提供)：铜代谢疾病(CMD)是一种以体内铜含量、分布或代谢异常为特征的异常疾病。这些疾病包括铜稳态所需的一个或多个调控步骤中的营养、获得性和遗传异常。这些疾病可能对患者造成严重后果，影响多个器官系统，并导致其他必需金属离子的生物可利用性异常。这些疾病通常很难诊断，努力了解基础金属生理学和病理生理学的科学家们对此非常感兴趣。铜相关疗法可能对癌症和其他疾病的治疗感兴趣。传统上，由于缺乏许多疾病的相关动物模型、可用于研究的铜同位素以及非侵入性、非破坏性和纵向评估铜在体内的动力学和分布的方法，对CMD的研究一直受到限制。最近的发展为规避这些限制提供了机会，包括许多特定CMD的新型啮齿动物模型的表征、微PET(正电子发射断层扫描)技术、具有半衰期的正电子发射体铜的可用性，以及允许从几个小时到几天的纵向研究(由美国国立卫生研究院支持的圣路易斯华盛顿大学国家研究资源提供)。将利用MicroPET成像和-铜在遗传获得性CMD啮齿动物模型中的体外生物分布研究来确定不同的成像表型是否定义了具有良好特征的CMD遗传性啮齿动物模型，以及通过新的治疗方法抢救特定疾病的表型是否使成像表型正常化。这些试点数据将被用来证明RO1应用的合理性，以探索诊断CMD的非侵入性方法，了解导致这些疾病的潜在病理生理学，并评估基于铜的新型疗法的有效性。在动物模型中建立CMD的成像表型对于非侵入性、非破坏性和纵向方法评估新的基因疗法也是至关重要的，这些新的基因疗法旨在逆转或改善导致CMD的缺乏或异常基因产物的后果。这些成像工具将对许多当地和地区性研究人员有用，这些研究人员将处理正常和异常的铜代谢、由此导致的疾病以及这些疾病患者的治疗。

DESCRIPTION (provided by applicant): Copper metabolism disease (CMD) is represents a spectrum of abnormalities characterized by abnormal content, distribution or metabolism of copper in the body. These diseases include nutritional, acquired and genetic abnormalities in one or more of the regulatory steps required in copper homeostasis. These diseases can have serious consequences to the patient, affecting multiple organ systems and resulting in abnormalities in the bioavailability of other essential metal ions. The diseases are often difficult to diagnose, and are of great interest to scientists who strive to understand basic metallophysiology and pathophysiology. Copper-related therapies may be of interest in the treatment of cancer and other diseases. Studies of CMD have traditionally been limited by the lack of relevant animal models for many of the diseases, the availability of Cu isotopes for research, and methods to non-invasively, non-destructively and longitudinally assess the kinetics and distribution of copper in the body. Recent developments have provided opportunities to circumvent these limitations, including the characterization of many novel rodent models of specific CMD's, the technology of microPET (positron emission tomography), the availability of Cu-64, a positron emitter with a half life permissive of longitudinal studies from hours to days (provided by an NIH-supported National Research Resource by Washington University, St. Louis). MicroPET imaging, and ex-vivo biodistribution studies of 64-Cu in rodent models of genetically acquired CMD will be utilized to establish whether distinct imaging phenotypes define well-characterized inherited rodent models of CMD's, and whether phenotypic rescue of specific disorders by novel therapies normalizes the imaging phenotype. These pilot data will be used to justify RO1 applications to explore non-invasive methods to diagnose CMD's, to understand the underlying pathophysiology that contributes to these disorders, and to assess the efficacy of novel copper- based therapies. The establishment of the imaging phenotypes of CMD in animal models is also critical to enable non-invasive, non-destructive and longitudinal methods for evaluating novel gene therapies designed to reverse or ameliorate the consequences of lacking or abnormal gene products that contribute to CMD. These imaging tools will be of use to numerous local and regional investigators addressing normal and abnormal copper metabolism, its resultant diseases and treatment of patients with these disorders.