Copper is an essential trace element that plays a fundamental role in the biochemistry of aerobic organisms. The long-term objective of these studies is to elucidate the biological roles of copper in human nutrition. Copper has a critical role in early human development, as evidenced by patients with Menkes disease, a fatal neurodegenerative disorder of childhood resulting from loss of function of a copper transport P-type Atpase. Despite the considerable clinical and experimental data indicating a role for copper in early embryonic development, the mechanisms and timing of the critical events affected by copper remain poorly understood, as experimental systems to elucidate the role of specific nutrients in early embryonic development are limited. The studies in this proposal are intended to utilize the zebrafish, Danio rerio, as a model organism to elucidate the role of copper in early development and to define the cellular and molecular determinants critical to this process. The precise molecular phenotype of copper deficiency in the developing zebrafish will be determined following treatment of embryos with a small molecule that interferes with copper delivery to the developing blastoderm. Specific genes involved in copper homeostasis and function that are critical for prenatal development will be identified by cloning and characterizing the copper phenotype mutants pinky and calamity and by performing a forward genetic screen for novel genes involved in embryonic copper metabolism. Finally, information derived from these studies will be utilized to develop novel therapeutic approaches for patients with Menkes disease by developing a fish model of this disease and performing a high-throughput chemical genomic screen to identify small molecules that will rescue the phenotype of the affected mutants. Taken together, the results of these studies will permit new insights into the role of copper in prenatal development and may allow for the discovery of novel therapeutic approaches to the prevention and treatment of birth defects arising from impaired copper homeostasis. In terms of

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, recent data indicate that structural birth defects may arise from impaired nutrition during human development, offering the possibility that the incidence of these disorders might be reduced by maternal dietary modification. This work will increase our understanding of the role of nutrition in human fetal development and provide new insights into the complex interplay of nutrition and genetics in the causation of human congenital malformations.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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Marine Biological Laboratory
Woods Hole
United States
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Soma, Shivatheja; Latimer, Andrew J; Chun, Haarin et al. (2018) Elesclomol restores mitochondrial function in genetic models of copper deficiency. Proc Natl Acad Sci U S A 115:8161-8166
Hodgkinson, Victoria L; Zhu, Sha; Wang, Yanfang et al. (2015) Autonomous requirements of the Menkes disease protein in the nervous system. Am J Physiol Cell Physiol 309:C660-8
Wang, Yanfang; Zhu, Sha; Hodgkinson, Victoria et al. (2012) Maternofetal and neonatal copper requirements revealed by enterocyte-specific deletion of the Menkes disease protein. Am J Physiol Gastrointest Liver Physiol 303:G1236-44
Wang, Yanfang; Zhu, Sha; Weisman, Gary A et al. (2012) Conditional knockout of the Menkes disease copper transporter demonstrates its critical role in embryogenesis. PLoS One 7:e43039
van Boxtel, Antonius L; Gansner, John M; Hakvoort, Henk W J et al. (2011) Lysyl oxidase-like 3b is critical for cartilage maturation during zebrafish craniofacial development. Matrix Biol 30:178-87
Mendelsohn, Bryce A; Malone, James P; Townsend, R Reid et al. (2009) Proteomic analysis of anoxia tolerance in the developing zebrafish embryo. Comp Biochem Physiol Part D Genomics Proteomics 4:21-31
Gansner, John M; Madsen, Erik C; Mecham, Robert P et al. (2008) Essential role for fibrillin-2 in zebrafish notochord and vascular morphogenesis. Dev Dyn 237:2844-61
Gansner, John M; Gitlin, Jonathan D (2008) Essential role for the alpha 1 chain of type VIII collagen in zebrafish notochord formation. Dev Dyn 237:3715-26
Thiele, Dennis J; Gitlin, Jonathan D (2008) Assembling the pieces. Nat Chem Biol 4:145-7
Madsen, Erik C; Morcos, Paul A; Mendelsohn, Bryce A et al. (2008) In vivo correction of a Menkes disease model using antisense oligonucleotides. Proc Natl Acad Sci U S A 105:3909-14

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