PROJECT SUMMARY/ABSTRACT The primary goal of this proposal is to provide a framework of methodologically-diverse, and clinically-inclined, investigative training that will prepare the principal investigator for a successful career as a translational physician-scientist. In addition to MD/PhD-specific professional development and expanded clinical/translational training, much of this preparation will come from technical education gained from the execution of this proposal’s research aims. These aims seek to broadly understand the placental correlates of fetal congenital heart defects (CHDs) in pregnancies affected by pregestational maternal diabetes mellitus (DM). It is recognized that the placenta plays a critical role in the development of fetal CHDs in early pregnancy, although this role is poorly understood. DM-affected pregnancies also have a pronounced phenotype of placental dysfunction, although the mediators of this also remain unknown. Additionally, DM-affected pregnancies are at substantially elevated risk of developing fetal CHDs and, for certain subtypes of CHD, carry an RR as high as 13.8. These CHDs represent a large percentage of critical and surgery-necessitating defects and are particularly high-burden, as they come with risk of additional malformations, neonatal hypoglycemia, preterm birth, and other perinatal complications. These complications, many of which are also seen in DM pregnancies, come downstream of cyclical exacerbations of placental dysfunction due to CHD-induced fetal hemodynamic changes. Given this, investigation of the pronounced changes in placental function seen in DM and/or CHD-affected pregnancies could yield extremely impactful information for both diagnostic and prognostic management of CHDs in diabetic pregnancies. The identification of pathway-level molecular changes, and their clinical associations, in pregnancies affected by DM, fetal CHDs, and both (DM+CHD) will produce novel and foundational information that could change the paradigm of perinatal care in these pregnancies. The overarching hypothesis of this project is that similar profiles of angiogenic and inflammatory molecular dysfunction, and resulting clinical pathology, will be observed in both maternal DM-affected and fetal CHD-affected pregnancies, and that this dysfunction will be particularly exacerbated in DM-affected pregnancies that also develop fetal CHD. This hypothesis will be tested via two aims. One aim will use large-scale institutional health data to assess the perinatal risk of common obstetric and neonatal complications in DM+CHD pregnancies relative to those affected by either pathology in isolation. The other will characterize the cell type-specific molecular dysfunction of DM, CHD, and DM+CHD placentas using high-throughput RNA sequencing, western blotting, and immunohistochemistry. In completing this training plan, and the scientific aims it includes, the applicant will receive critical didactic and experiential training neces...