Mechanisms of maternal hyperglycemia induced risk of congenital heart disease

Doctor's Name: 
Madhumita Basu
Nationwide Children's Hospital

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards (Total Grant Amount $249,480; CHF portion = $124,740)

SUMMARY: Congenital heart disease (CHD) is the leading cause of childhood morbidity and mortality. The complex inheritance pattern and multifactorial etiologies of CHD make it difficult to explain a significant fraction of cases. Apart from genetic contributors, maternal intrauterine environment play an indispensable role in CHD susceptibility among infants. Maternal pre-existing diabetes mellitus (matDM) is one of the non-genetic risk factor that affects cardiac morphogenesis. In a recent study utilizing murine model of type1 diabetes, we demonstrated gene-environment interaction between matDM and Notch1 haploinsufficiency increases the incidence of ventricular septal defects in E13.5 embryos. In vitro studies showed loss of chromatin accessibility at Nos3 loci causes reduced nitric oxide production and increases expression of Jarid2, a repressor of Notch1. Interestingly, elevated levels of maternal hyperglycemia (HG) results in a spectrum of malformations ranging from several defects in outflow tract and cushion development which indicates perturbed interactions between diverse cell types of different functional and embryonic origins. However, the dose-response relationship between HG levels and severity of CHD and underlying molecular mechanisms of cell lineage specific sensitivity to HG is unclear. The current proposal is divided into 3 specific aims. Aim 1 will utilize a chemically-induced type1 matDM murine model to investigate the severity of maternal HG on developing embryos (E9.5, E11.5, E13.5 and E15.5). Combination of morphometric and RNA-seq analysis will define intracellular signaling pathways that control cellular viability and neural crest cell migration in diabetic pregnancies. Aim 2 will elucidate the dose-response relationship of HG on endocardial and neural crest cells. In vitro experiments will be performed on ECC-1, AVM and O9-1 cells cultured in four different concentrations of glucose. RNA-seq and ATAC-seq analysis will identify cell specific transcriptional regulatory factors and epigenetic mechanisms altered in HG stress. Finally, Aim 3 will examine insulin-mediated rescue in phenotypic severity of matDM associated CHDs using similar model. Rescue in cell proliferation, apoptosis and migration defects will be assessed in vivo across developmental timepoints. Together, this proposal will delineate precise molecular and cellular mechanism of dose-dependent severity in CHD phenotypes in the setting of maternal hyperglycemic environment    

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