Prenatal exposure of the fetus to pregnancy-related disorders, including preeclampsia (PE), intrauterine growth restriction (IUGR) and gestational diabetes, leads to long-term consequences, such as hypertension, cardiovascular disease or diabetes, later in life. This phenomenon is known as fetal programming. Placental membrane transporters and their regulation affect the intrauterine environment and, therefore, may play a crucial role in the process of fetal programming. New insights in placental transport systems and their role in fetal programming will help to develop prophylactic strategies to prevent the long-term consequences of these pregnancy-specific diseases.
Calcium was shown to play a role in the pathogenesis of PE, a pregnancy-specific disease characterized by hypertension and proteinuria. The placental calcium transport system has an impact on the intrauterine environment, which in turn increases the risk for cardiovascular diseases later in life. Uric acid is also involved in the pathogenesis of PE. Hyperuricemia, commonly observed in PE, is associated with adverse perinatal outcome. In addition, materno-fetal glucose transport is crucial for the fetal well-being. Glucose, which is delivered from the mother to the fetus across the placenta, is the most important energetic substrate for the fetus. Under hypoxic conditions the fetus produces ATP by anaerobic glycolysis. A variety of pregnancy-specific diseases, often associated with hypoxia, have short- and long-term sequelae for both the mother and child including intrauterine death, asphyxia and an elevated risk for cardiovascular diseases. GLUT1 is the only relevant placental glucose transporter during the second and third trimester. Previous studies of the Surbek/Baumann group revealed that glucose transport activity and the expression of its only relevant glucose transporter GLUT1 in the placenta at term is increased upon hypoxia.
In project 9A, the Surbek/Baumann group is focusing their research activities on TRPV6, DMT1, GLUT9, and GLUT1 in context of a variety of pregnancy-specific diseases such as e.g. PE, IUGR, and gestational diabetes. The group investigates whether altered target protein expression in the placenta, e.g. by hypoxia or nutrient availability, affects placental substrate transport activity. To this end, placental target protein expression will be assessed, as well as transport studies established in vitro and ex vivo. In parallel, compounds generated in collaboration with TransCure chemists and derived from own screening efforts (e.g. GLUT1 and GLUT9) and other projects within TransCure (e.g. TRPV6 and DMT1) will be assessed for their therapeutic efficacy in vitro, ex vivo and in vivo.