Status: Funded - Open
Finding new therapies for improving placental function in preeclampsia
Jessica Saben, Ph.D.
BACKGROUND: Preeclampsia (PE), a disorder that affects 5-8% of all pregnancies, is marked by maternal hypertension and proteinuria. The only treatment is delivery of the baby, often prematurely, which can have lifelong health and neurodevelopmental consequences for the child.
GAP: Although the causes are unclear, preeclampsia appears to be a consequence of improper formation of the placenta, the transitory organ responsible for maternal-fetal exchange of nutrients, oxygen, and wastes. Placentas from preeclamptic pregnancies also produce excess uric acid, which may contribute to the etiology of this disease; however, the mechanisms by which placentas accumulate uric acid and whether prevention of uric acid accumulation can prevent placental dysfunction associated with preeclampsia remain unknown.
HYPOTHESIS: We hypothesize that increased placental fructose metabolism drives intracellular uric acid production, resulting in elevated oxidative stress and cellular dysfunction.
METHODS: Fructose metabolism, uric acid production, and oxidative stress will be measured in the placentas from preeclamptic and normal-healthy controls matched for gestational age (≥ 36 weeks), birth weight, maternal body mass index, and race obtained from the Women and Infants’ Health Specimen Consortium at Washington University. Two therapies that block the fructose-uric acid-oxidative stress pathway will be tested for their ability to rescue dysfunction in trophoblasts from preeclamptic placentas
IMPACT: Results from this work will 1) advance our knowledge of mechanisms that drive placental dysfunction in PE, and 2) may provide evidence to support preclinical studies and clinical trials of two therapies (both of which are already used in humans) to improve placental function. Although such trials would require several years to complete, development of a therapeutic could prevent PE or greatly improve health outcomes of children born to PE mothers.