TOMOGRAPHIC DETERMINATION OF ZEBRAFISH METAL DISTRIBUTIONS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Copper is an essential transition metal that plays a critical role in the biochemsitry of aerobic organisms. Gitlin and co-workers (submitted) have developed a chemical genetic screen for identifying small molecules that selectively perturb copper homeostasis in zebrafish. This has allowed the identification of several molecules that can be used to selectively alter Cu concentration in developing zebrafish embryos, thus providing insight into the developmental pathophysiology of copper metabolism, suggesting ways in which suboptimal copper metabolism may contribute to birth defects. For example, they have found an adaptive hierachy of copper metabolism, with treatments for different lengths of time and/or with different concentration of inhibitor, affecting first melanin pigmentation, then ventricle size, then notochord development. This behavior reproduces the pathology observed in human Menkes-disease patients. We propose to use x-ray microprobe imaging to determine the distribution and concentration of all of the essential trace elements (V, Mn, Fe, Co, Ni, Cu, and Zn) in zebrafish embryos as a function of selective Cu depeletion at various times during development. Previous studies (e.g., in yeast models) have revealed a complex set of interactions between the concentrations of different essential metals, and thus it is important to explore the full distribution of different essential trace elements under different conditions of Cu stress.