The lack of a whole animal model that recapitulates the phenotype of patients with classic galactosemia has hindered the progress of research on this disease for decades. Indeed, despite more than 50 years of investigation, the mechanisms underlying the pathophysiology of both classic and epimerase- deficiency galactosemia remain unclear, and while neonatal diagnosis and life-long dietary restriction of galactose resolve or prevent the acute and potentially lethal symptoms, most treated patients nonetheless go on to experience devastating complications. The long-term goal of our research is to define those mechanisms that underlie the pathophysiology of both classic and epimerase-deficiency galactosemia, and to apply that knowledge toward the development of novel and more effective treatments for both disorders. Over the past 15 years, we have worked with yeast and mammalian tissue culture systems to define the impact of GALT and GALE impairment on biochemical and cellular functions. The scope of this work has been constrained, however, by the limitations of each model. With this application we propose to overcome those limitations by studying GALT and GALE function in a well-established whole-animal model, the fruit fly Drosophila melanogaster. In a substantial body of preliminary work we have demonstrated that loss of Drosophila GALT (DgalT) or GALE (DgalE) recapitulates significant aspects of the acute human phenotype of galactosemia. This fly model of galactosemia stands in welcome contrast to the GALT knockout mouse, first reported by Leslie and colleagues in 1996, which fails to recapitulate either the acute or the long-term complications of galactosemia. Our short-term goals are to: (1) Define the organismal and tissue-specific roles of DgalT and DgalE in Drosophila development and homeostasis, (2) Use Drosophila as a model system to test genotype/phenotype correlation in GALT- and GALE-deficiency galactosemia, and (3) Identify modifiers of outcome in DgalT- and DgalE-impaired Drosophila. Classic galactosemia is a potentially lethal disease affecting at least 100 infants born each year in the US alone;despite neonatal diagnosis and lifelong dietary intervention, the majority of these patients go on to experience devastating long-term complications. The goal of the proposed work is to apply a Drosophila melanogaster animal model system to define the role of galactose metabolism in normal development and homeostasis, and to identify the bases of pathophysiology in galactosemia. The results of this work will not only empower basic and translational studies aimed at improving treatment in galactosemia, but also will set a powerful precedent for application of this model system to the study of other metabolic disorders for which no appropriate animal model yet exists.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG1-GTIE-A (01))
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Mckeon, Catherine T
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Emory University
Schools of Medicine
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Daenzer, Jennifer M I; Jumbo-Lucioni, Patricia P; Hopson, Marquise L et al. (2016) Acute and long-term outcomes in a Drosophila melanogaster model of classic galactosemia occur independently of galactose-1-phosphate accumulation. Dis Model Mech 9:1375-1382
Jumbo-Lucioni, Patricia P; Ryan, Emily L; Hopson, Marquise L et al. (2014) Manganese-based superoxide dismutase mimics modify both acute and long-term outcome severity in a Drosophila melanogaster model of classic galactosemia. Antioxid Redox Signal 20:2361-71
Jumbo-Lucioni, Patricia P; Hopson, Marquise L; Hang, Darwin et al. (2013) Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia. Dis Model Mech 6:84-94
Spencer, Jessica B; Badik, Jennifer R; Ryan, Emily L et al. (2013) Modifiers of ovarian function in girls and women with classic galactosemia. J Clin Endocrinol Metab 98:E1257-65
Ryan, Emily L; Lynch, Mary Ellen; Taddeo, Elles et al. (2013) Cryptic residual GALT activity is a potential modifier of scholastic outcome in school age children with classic galactosemia. J Inherit Metab Dis 36:1049-61
Daenzer, Jennifer M I; Sanders, Rebecca D; Hang, Darwin et al. (2012) UDP-galactose 4'-epimerase activities toward UDP-Gal and UDP-GalNAc play different roles in the development of Drosophila melanogaster. PLoS Genet 8:e1002721
Ryan, Emily L; DuBoff, Brian; Feany, Mel B et al. (2012) Mediators of a long-term movement abnormality in a Drosophila melanogaster model of classic galactosemia. Dis Model Mech 5:796-803
McCorvie, Thomas J; Wasilenko, Jamie; Liu, Ying et al. (2011) In vivo and in vitro function of human UDP-galactose 4'-epimerase variants. Biochimie 93:1747-54
Sanders, Rebecca D; Sefton, Jennifer M I; Moberg, Kenneth H et al. (2010) UDP-galactose 4' epimerase (GALE) is essential for development of Drosophila melanogaster. Dis Model Mech 3:628-38
Kushner, Rebekah F; Ryan, Emily L; Sefton, Jennifer M I et al. (2010) A Drosophila melanogaster model of classic galactosemia. Dis Model Mech 3:618-27

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