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 project is formulated on the basis of our strong preliminary data. We have found 1) maternal diabetes impairs autophagy and increases the accumulation of defective mitochondria, dysfunctional proteins and swollen endoplasmic reticulum (ER) in the developing neuroepithelium;2) the non-toxic autophagy activator, trehalose, reverses diabetes-induced autophagy impairment and neural tube defects (NTDs);3) Fluorescein isothiocyanate (FITC)-labeled trehalose binds to autophagy promoting factors, Beclin-1 and ATG12, and induces selective autophagy;4) PKCa gene deletion, a p70S6K1 inhibitor and overexpression of an autophagy promoting factor, AMBRA1, in the neural tube, all reduce diabetes-induced NTDs. We test a novel hypothesis that trehalose activates autophagy by re- assembling diabetes-disrupted autophagy initiating complexes, removing the p70S6K1's inhibition and restoring AMBRA1 expression. Both deletion of the S6K1 gene and overexpression of the AMBRA1 gene in the neuroepithelium re-activate autophagy and restore cellular homeostasis leading to NTD prevention.
Aim 1 will determine the mechanisms underlying trehalose induction of selective autophagy and restoration of cellular homeostasis leading to prevention of diabetic embryopathy. We hypothesize that trehalose re-activates autophagy by facilitating the formation of the PI3KC3-Beclin-1-AMBRA1 complex and enhancing LC3-I lipidation to form LC3-II. Furthermore, trehalose-induced mitophagy and reticulophagy selectively remove defective mitochondria and stressed ER.
Aim 2 will determine how trehalose removes p70S6K1's inhibition on autophagy and the mechanism underlying p70S6K1-mediated diabetic embryopathy. Our working hypothesis is that trehalose removes p70S6K1's inhibition on autophagy initiating complexes by disrupting the association between p70S6K1 and Beclin-1, and that protein kinase C alpha (PKCa) activates p70S6K1, which is responsible for impaired autophagy and NTD formation in diabetic embryopathy.
Aim 3 will determine the regulatory mechanism of AMBRA1 expression and its role in autophagy and NTD prevention in diabetic embryopathy. We will test the hypothesis that trehalose restores AMBRA1 expression by increasing its mRNA stability, and that restoring AMBRA1 expression is sufficient to re-activate autophagy, which prevents NTD formation in diabetic pregnancies.
Nearly three million American women at reproductive ages have diabetes and this number will be double by 2030. This project will provide a mechanistic basis for exploring the non-toxic autophagy activator, trehalose, as a new prevention strategy against diabetes-induced neural tube defects.
|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|
|Zilberman-Rudenko, Jevgenia; McCarty, Owen J T (2017) Utility and development of microfluidic platforms for platelet research. Platelets 28:425-426|
|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; Wang, Shengbing; Shen, Wei-Bin et al. (2017) The current status and future of cardiac stem/progenitor cell therapy for congenital heart defects from diabetic pregnancy. Pediatr Res :|
|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|
|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|
|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|
|Dong, Daoyin; Zhang, Yuji; Reece, E Albert et al. (2016) microRNA expression profiling and functional annotation analysis of their targets modulated by oxidative stress during embryonic heart development in diabetic mice. Reprod Toxicol 65:365-374|
|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|
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