Imaging phenotypes in copper metabolism disease in mice

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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.