Project Description

Mothers with pre-gestational type 1 diabetes mellitus (pre-T1DM) are three to five times more likely than non-diabetic mothers to give birth to babies with heart defects. During the first trimester, high blood glucose can perturb normal heart development in the fetuses and lead to cardiac malformations. Despite the well-known causes of pre-T1DM, the mechanistic evidence for its effects on pregnancy is still lacking. Profound metabolic changes occur during diabetic pregnancy; for example, insulin and fat levels are usually altered. The mother also experiences higher levels of reactive oxygen species (ROS) – unstable chemicals that can negatively impact the body.

However, hyperglycemia is thought to be the primary factor that negatively affects the fetal cardiac development. Therefore, using a rodent model of pre-T1DM, our group has previously demonstrated the gene-environment interaction between maternal hyperglycemia and deletion or insufficiency of key cardiac genes which increase the risk of congenital heart defects.

The heart is the first organ to develop in the fetus. It is a non-uniform tissue, composed of numerous cell types and millions of cells. Recently, using a single-cell gene-expression analysis in developing embryonic hearts, we described significant gene expression changes in multiple cardiac cell populations. Specialized cardiac precursor cells were found to be highly sensitive to maternal hyperglycemia, as shown by differences in gene expression compared to embryonic hearts from non-diabetic mothers. Based on this preliminary observation, the overarching goal of our research program is designed to characterize how metabolic and epigenetic changes in cardiac progenitor cells contribute to heart defects in diabetic offspring.

We hypothesize that nutrient availability and fetal nutrient usage in pre-T1DM pregnancy reprogram cardiac precursor cells and “reset” their mechanisms of regulating key genes. In order to address this question, we will determine the mechanism of how cardiac precursor cells respond to metabolic dysfunction and then rearrange their gene regulatory systems. Tracking the development of cardiac progenitor cells – and their descendants during fetal heart development – is expected to unravel the mechanisms by which pre-T1DM affects heart development, as well as the relative risk each specific cell population experiences. An increased understanding of how maternal pre-T1DM induces cardiovascular defects will allow for the development of effective treatment that mitigates the effect of diabetes on fetuses.