Investigating the Role of Thyroid Hormone in Placental Function

Investigating the Role of Thyroid Hormone in Placental Function Thyroid hormone (TH) is necessary to support both fetal and placental development during pregnancy. Maternal supply of TH to the fetus early in pregnancy is necessary before the fetus can produce TH itself, which starts around 16 weeks of gestation with significant TH secretion not occurring until 18-20 weeks. The placenta uses thyroid hormone to regulate metabolic processes, which includes using 60-80% of the oxygen and glucose it takes up from the maternal circulation. Impaired placental development and function is an underlying cause of fetal growth restriction (FGR), which is a significant cause of infant morbidity and mortality. The causation and progression of placental insufficiency is not well understood and requires studies that investigate the mechanisms of placental function. It is difficult to directly address these questions in humans, predicating the need for relevant animal models. Regulation of placental function by thyroid hormone during pregnancy is complex with the potential to regulate proliferation, differentiation, hormone production, invasion and angiogenesis. Major gaps exist in our understanding of how T3 and T4 are used by the placenta to regulate placenta metabolism and function, and further how the placenta regulates transport of T4 through the placenta to fetal circulation. TH function by the placenta is regulated by iodothyronine deiodinase type II (DIO2) which converts T4 to active T3, supporting placental growth and oxidative processes. Iodothyronine deiodinase type III (DIO3) converts T4 to an inactive form, reverse T3 (rT3). DIO3 will both inactivate TH within the placenta and limit the amount of T4 that can pass through the placenta to the fetus, however, this has not been tested in vivo. Clearly the uptake, transport and activity of TH within the placenta is complex, and needs clarification, especially during the first half of gestation when the placenta is rapidly developing, and the fetus is dependent on maternal derived TH. It is our long-term goal to determine the causes behind impaired placental function, and how placental-insufficiency manifests itself in FGR. Historically, the pregnant sheep has provided considerable insight into in vivo placental substrate uptake, utilization and transfer to the developing fetus. Herein, we will test our central hypothesis that impairment of trophoblast expression of either DIO2 or DIO3 will result in significant placental and fetal growth restriction by mid-gestation, setting the stage for functional placental insufficiency (PI) and FGR. In aim 1 we will test the hypothesis that DIO2 deficiency will result in impaired placental development and significant FGR by mid-gestation (75 dGA). In aim 2 we will test the hypothesis that DIO3 gain-of-function will result in decreased placental transport of T4 across the placenta to the fetus, a hypothyroid fetus and significant FGR by mid-gestation (75 dGA). Use of lentiviral mediated RNA interference of DIO2 and gain-of-function of DIO3 will test our central hypothesis and provide a unique animal model to assess the in vivo physiological function of placental thyroid hormone. Project Number: 1R21HD115058-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Quinton Winger | Institution: COLORADO STATE UNIVERSITY, FORT COLLINS, CO | Award Amount: $423,500 | Activity Code: R21 | Study Section: Pregnancy and Neonatology Study Section[PN] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HD11505801A1