Diabetic embryopathy is a diabetic complication in which the early embryo of a mother with diabetes develops congenital malformations. The proposed experiments employ a mouse model of diabetic pregnancy in which expression of genes which control essential developmental processes is disturbed. These experiments focus on Pax3, a gene whose expression is significantly reduced in embryos of diabetic mice, which encodes a transcription factor required for development of structures that are often malformed during diabetic embryopathy, especially the neural tube and the heart. In the previous funding period, we showed that maternal hyperglycemia increases glucose delivery to the embryo, and that oxidative and hypoxic stress, resulting from excess glucose metabolism, causes impaired Pax3 expression, thereby leading to neural tube defects (NTD). In addition to experiments using embryos, we have used murine embryonic stem (ES) cells, which can be grown in quantity and can be induced to a Pax3-expressing neuroepithelial cell type. The central hypothesis to be tested in this proposal is that biochemical pathways affected by increased glucose metabolism by the early embryo causes oxidative and hypoxic stress, which prevents the induction or binding of transcription factors that activate expression of essential developmental control genes. In this proposal we will: (1) Investigate the interaction of hypoxic stress, oxidative stress, and increased protein kinase C activity leading to impaired Pax3 expression;(2) Identify factors which bind to a Pax3 regulatory element that is needed for differentiation-induced expression and which is inhibited by oxidative stress;and (3) Test the hypothesis that the same biochemical disturbances that lead to impaired Pax3 expression in mouse ES cells also lead to impaired PAX3 expression in human ES cells. Relevance: Understanding how maternal diabetes disturbs early embryonic development on a biochemical and molecular level is essential in order to devise new strategies to prevent them. The proposed research will use a mouse model of diabetic pregnancy and mouse embryonic stem cells to elucidate the biochemical mechanisms by which important embryonic gene expression is disturbed, and human embryonic stem cells to determine the extent to which the mouse and mouse stem cells serve as a model for the effects of biochemical disturbances during human diabetic pregnancy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Jones, Teresa L Z
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Joslin Diabetes Center
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Jung, Jin Hyuk; Iwabuchi, Kumiko; Yang, Zhihong et al. (2016) Embryonic Stem Cell Proliferation Stimulated By Altered Anabolic Metabolism From Glucose Transporter 2-Transported Glucosamine. Sci Rep 6:28452
Loeken, Mary R (2014) Opportunities and challenges for repair of macrovascular disease using circulating blood-derived progenitor cells. Diabetes Metab Res Rev 30:554-5
Wei, Dan; Loeken, Mary R (2014) Increased DNA methyltransferase 3b (Dnmt3b)-mediated CpG island methylation stimulated by oxidative stress inhibits expression of a gene required for neural tube and neural crest development in diabetic pregnancy. Diabetes 63:3512-22
Lee, Hyung-Yul; Wei, Dan; Loeken, Mary R (2014) Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy. Diabetes Metab Res Rev 30:23-30
Loeken, Mary R (2014) Intersection of complex genetic traits affecting maternal metabolism, fetal metabolism, and neural tube defect risk: looking for needles in multiple haystacks. Mol Genet Metab 111:415-7
Sanders, Kaitlyn; Jung, Jin Hyuk; Loeken, Mary R (2014) Use of a murine embryonic stem cell line that is sensitive to high glucose environment to model neural tube development in diabetic pregnancy. Birth Defects Res A Clin Mol Teratol 100:584-91
Loeken, Mary R (2012) A new role for pancreatic insulin in the male reproductive axis. Diabetes 61:1667-8
Wu, Y; Viana, M; Thirumangalathu, S et al. (2012) AMP-activated protein kinase mediates effects of oxidative stress on embryo gene expression in a mouse model of diabetic embryopathy. Diabetologia 55:245-54
Zabihi, Sheller; Loeken, Mary R (2010) Understanding diabetic teratogenesis: where are we now and where are we going? Birth Defects Res A Clin Mol Teratol 88:779-90
Chappell Jr, James H; Wang, Xiao Dan; Loeken, Mary R (2009) Diabetes and apoptosis: neural crest cells and neural tube. Apoptosis 14:1472-83

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