The hypothesis in this project is that Glut3 expression is critical for neuronal glucose supply through development, and that Glut3 plays an essential role in hypoxic-ischemic cellular apoptosis and necrosis. The primary goals are to determine the essential regulatory elements in the murine Glut3 gene that confer neuronal specificity, and susequently to determine the role of Glut3 in hypoxic-ischemic brain injury. First, the essential regulatory elements in the gene that confer neuronal specificity will be characterized by 5'-serial deletions of Glut3-1acZ reporter gene constructs, transiently transfecting the constructs into the mouse neuronal and nonneuronal cell lines, creating transgenic mice harboring Glut3-1acZ fusion genes to confirm the in vitro and in vivo functional role of the cis-elements that confer cell specificity, and to determine their role in hypoxic-ischemic brain injury. Second, the Glut3 gene will be overexpressed in neuronal cells and its role in apoptosis and necrosis determined. This will be done by stable transfection of Glut3 gene in neuronal cells and by generation of transgenic mice harboring multiple copies of Glut3 gene under the control of the neuron-specific synapsin I promoter. Third, neuron-specific Glut3 knockout mice will be generated using the Cre/LoxP recombination strategy to examine the influence of Glut3 ablation on hypoxic-ischemic brain injury.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD033997-04
Application #
2751715
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Grave, Gilman D
Project Start
1995-09-01
Project End
2004-06-30
Budget Start
1999-07-26
Budget End
2000-06-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Calkins, Kara L; Thamotharan, Shanthie; Dai, Yun et al. (2018) Early dietary restriction in rats alters skeletal muscle tuberous sclerosis complex, ribosomal s6 and mitogen-activated protein kinase. Nutr Res 54:93-104
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Chen, Yongjun; Shin, Bo-Chul; Thamotharan, Shanthie et al. (2014) Differential methylation of the micro-RNA 7b gene targets postnatal maturation of murine neuronal Mecp2 gene expression. Dev Neurobiol 74:407-425
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Chen, Yongjun; Shin, Bo-Chul; Thamotharan, Shanthie et al. (2013) Creb1-Mecp2-(m)CpG complex transactivates postnatal murine neuronal glucose transporter isoform 3 expression. Endocrinology 154:1598-611
Thamotharan, Shanthie; Stout, David; Shin, Bo-Chul et al. (2013) Temporal and spatial distribution of murine placental and brain GLUT3-luciferase transgene as a readout of in vivo transcription. Am J Physiol Endocrinol Metab 304:E254-66
Londhe, Vedang A; Maisonet, Tiffany M; Lopez, Benjamin et al. (2013) Retinoic acid rescues alveolar hypoplasia in the calorie-restricted developing rat lung. Am J Respir Cell Mol Biol 48:179-87

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