Research Projects

Gestational diabetes mellitus (GDM) is a significant risk factor for both pregnant mothers and their offspring. Traditionally defined as “impaired glucose tolerance with first onset/recognition during pregnancy”, GDM is correlated with negative outcomes in both the mothers and the offspring. While mothers have an increased risk of developing type 2 diabetes and cardiovascular complications, the offspring have an increased risk of obesity as well as congenital heart diseases. Maternal hyperglycemia, i.e., high blood glucose levels, in the first trimester when the fetal heart is developing, is known to affect fetal cardiac development and function. This project aims to establish an in vitro organoid system to model the earliest steps of cardiac development and examine the effects of the hyperglycemia seen in diabetic mothers on fetal heart development. Key objectives: 1) To establish a mouse cardioid model to recapitulate the earliest steps of cardiac development. The differentiation strategy for the cardioid model will be designed using information from in vivo studies, to exactly recapitulate the developmental process. The cardiac chambers can be studied in isolation or fused to form multi-chamber cardioids. 2) To reveal the changes in fetal cardiogenesis caused by hyperglycemia in diabetic mothers. The mouse cardioid model will then be used to test the effects of hyperglycemia on the transcriptome at stages corresponding to the first trimester of pregnancy, to understand the molecular basis of affected fetal cardiac development and function in infants with diabetic mothers. Dysregulated signaling pathways and transcription factor function will be identified. 3) To validate the dysregulated molecular mechanisms as potential therapeutic targets. The mouse cardioids will finally be used to examine and validate potential therapeutic targets by comparison with both an in vivo mouse correlate (mouse embryos) as well as in human cardioids. I (the PI) have previous experience in successfully establishing in vitro models of cardiac development, as detailed in the research plan. The established mouse cardioid model will provide an efficient platform to screen the effects of a challenging environment during pregnancy, such as hyperglycemia in this case. More specifically, it will provide an in vitro/in vivo and cross-species comparison study of high glucose-induced changes on individual cardiac chambers during fetal heart development. The individual cardiac chambers – the left and right ventricles, and the left and right atria, are differentially impacted in congenital heart diseases, but it is unclear why. Results from this study can explain the basis of the congenital heart defects in infants born to diabetic mothers, and can provide a system to validate novel therapeutic targets.