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.
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.
|Dong, Daoyin; Zielke, Horst Ronald; Yeh, David et al. (2018) Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder. Autism Res 11:1076-1090|
|Zhong, Jianxiang; Wang, Shengbing; Shen, Wei-Bin et al. (2018) The current status and future of cardiac stem/progenitor cell therapy for congenital heart defects from diabetic pregnancy. Pediatr Res 83:275-282|
|Zhao, Yang; Dong, Daoyin; Reece, E Albert et al. (2018) Oxidative stress-induced miR-27a targets the redox gene nuclear factor erythroid 2-related factor 2 in diabetic embryopathy. Am J Obstet Gynecol 218:136.e1-136.e10|
|Gabbay-Benziv, Rinat; Reece, E Albert; Wang, Fang et al. (2017) A step-wise approach for analysis of the mouse embryonic heart using 17.6Tesla MRI. Magn Reson Imaging 35:46-53|
|Lin, Xue; Yang, Penghua; Reece, E Albert et al. (2017) Pregestational type 2 diabetes mellitus induces cardiac hypertrophy in the murine embryo through cardiac remodeling and fibrosis. Am J Obstet Gynecol 217:216.e1-216.e13|
|Chen, Xi; Zhong, Jianxiang; Dong, Daoyin et al. (2017) Endoplasmic Reticulum Stress-Induced CHOP Inhibits PGC-1? and Causes Mitochondrial Dysfunction in Diabetic Embryopathy. Toxicol Sci 158:275-285|
|Zhong, Jianxiang; Xu, Cheng; Reece, E Albert et al. (2016) The green tea polyphenol EGCG alleviates maternal diabetes-induced neural tube defects by inhibiting DNA hypermethylation. Am J Obstet Gynecol 215:368.e1-368.e10|
|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; 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|
Showing the most recent 10 out of 29 publications