The main objectives of the proposed reintegration research grant are: 1) to investigate the molecular causes of diabetic embryopathy; 2) to transfer my knowledge and experience to the Czech and European academia and industry; and 3) to develop a network of future international research collaboration dealing with diabetes. The scientific objective is to understand how maternal diabetes affects the developing embryo and increases the risk for heart malformations. The risk for birth defects is up to 10-fold higher in diabetic than in non-diabetic pregnancies. With increasing prevalence of diabetes in women of childbearing age, diabetes becomes a major cause of mortality and health problems in infants born to diabetic mothers. Although the teratogenic effects of maternal diabetes are well documented, the molecular causes remain elusive. Using global expression profiling, our team discovered that the exposure to maternal diabetes deregulated 126 genes in developing embryos. Many of these genes are already known to be involved in heart defects or affect heart functions. In this project I propose: 1) to define which genes can serve as predictive markers for specific abnormalities in heart development; 2) to determine cell-type specificity of diabetes-deregulated genes within the developing heart; 3) to identify specific time points, which are the most susceptible for induction of changes in the heart; and 4) to investigate the role of HIF1-controlled-hypoxia-response pathways in diabetic embryopathy. Understanding the molecular causes of diabetic embryopathy will form the basis for future strategies to prevent birth defects associated with diabetic pregnancies. The reintegration objectives will be achieved via my appointment as an independent Group Leader at the Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic, where I will be responsible for team building, training, teaching, and conducting high quality collaborative research.