Congenital malformations occur in up to 10% of babies born to diabetic women. Optimal glycemic control is difficult to achieve and maintain, and even transient exposure to hyperglycemia can cause malformations. This current proposal is formulated on the basis of our findings relative to the PKC pathway, which is critically involved i the induction of diabetic embryopathy. Because the molecular intermediates downstream PKC activation have not been determined, we have advanced a novel hypothesis that maternal hyperglycemia-induced PKCa/d activation reduces the expression of SIRT2 through DNA hypermethylation. SIRT2 downregulation prevents sustainable antioxidant enzyme expression and induces MARCKS hyperacetylation, which contributes to MARCKS phosphorylation. PKC-dependent SIRT2 downregulation and MARCKS phosphorylation in the developing neural tube are responsible for cellular stresses that cause neuroepithelial cell apoptosis and NTD formation.
Aim 1 will determine whether PKCa and PKCd suppress SIRT2 expression through DNA hypermethylation in diabetic embryopathy. We hypothesize that that PKCa and PKCd increases the expression of de novo DNA methyltransferases (DNMT3A/B), which induce hypermethylation in the SIRT2 promoter and inhibit its expression.
Aim 2 will determine the role of SIRT2 in PKC-induced cellular stress, MARCKS phosphorylation and NTD formation in diabetic embryopathy. Our working hypothesis is that downregulation of SIRT2 decreases antioxidant enzyme expression, which results in oxidative and endoplasmic reticulum stress, and leads to an increase in MARCKS acetylation and phosphorylation, which contributes to cellular stress.
Aim 3 will determine the causal role of MARCKS phosphorylation in diabetes-induced cellular stress, apoptosis and NTD formation. We will test the hypothesis that PKCa/d-dependent MARCKS phosphorylation induces cellular stress and mitochondrial dysfunction, resulting in apoptosis and NTD formation. The success of this project will significantly fill the gaps in the current knowledge base regarding events that cause diabetic embryopathy.

Public Health Relevance

Maternal diabetes is a significant risk factor for structural birth defects. Even with modern preconceptional care, diabetic women are three- to four-times more likely to have a child with birth defects than nondiabetic women. In this proposal, we will test th role of PKCa/d, SIRT2, MARCKS and DNA hypermethylation in NTD formation in diabetic pregnancies.

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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University of Maryland Baltimore
Obstetrics & Gynecology
Schools of Medicine
United States
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Dong, Daoyin; Reece, E Albert; Lin, Xue et al. (2016) New development of the yolk sac theory in diabetic embryopathy: molecular mechanism and link to structural birth defects. Am J Obstet Gynecol 214:192-202
Gu, Hui; Yu, Jingwen; Dong, Daoyin et al. (2016) High Glucose-Repressed CITED2 Expression Through miR-200b Triggers the Unfolded Protein Response and Endoplasmic Reticulum Stress. Diabetes 65:149-63
Dong, Daoyin; Fu, Noah; Yang, Peixin (2016) MiR-17 Downregulation by High Glucose Stabilizes Thioredoxin-Interacting Protein and Removes Thioredoxin Inhibition on ASK1 Leading to Apoptosis. Toxicol Sci 150:84-96
Zhong, Jianxiang; Xu, Cheng; Gabbay-Benziv, Rinat et al. (2016) Superoxide dismutase 2 overexpression alleviates maternal diabetes-induced neural tube defects, restores mitochondrial function and suppresses cellular stress in diabetic embryopathy. Free Radic Biol Med 96:234-44
Yang, Penghua; Chen, Xi; Kaushal, Sunjay et al. (2016) High glucose suppresses embryonic stem cell differentiation into cardiomyocytes : High glucose inhibits ES cell cardiogenesis. Stem Cell Res Ther 7:187
Yu, Jingwen; Wu, Yanqing; Yang, Peixin (2016) High glucose-induced oxidative stress represses sirtuin deacetylase expression and increases histone acetylation leading to neural tube defects. J Neurochem 137:371-83
Yang, Penghua; Shen, Wei-bin; Reece, E Albert et al. (2016) High glucose suppresses embryonic stem cell differentiation into neural lineage cells. Biochem Biophys Res Commun 472:306-12
Zhong, Jianxiang; Reece, E Albert; Yang, Peixin (2015) Punicalagin exerts protective effect against high glucose-induced cellular stress and neural tube defects. Biochem Biophys Res Commun 467:179-84
Wang, Fang; Wu, Yanqing; Quon, Michael J et al. (2015) ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development. Am J Physiol Endocrinol Metab 309:E487-99
Wang, Fang; Reece, E Albert; Yang, Peixin (2015) Oxidative stress is responsible for maternal diabetes-impaired transforming growth factor beta signaling in the developing mouse heart. Am J Obstet Gynecol 212:650.e1-11

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