This proposal will investigate the regulation of proliferation and invasion of human trophoblast cells by the pluripotency factor LIN28. Proliferation and differentiation of trophoblast cells is necessary during early stages of pregnancy to produce a healthy placenta. Inadequate trophoblast invasion results in placental pathologies including preeclampsia and placental insufficiency resulting in fetal intrauterine growth restriction (IUGR). Preeclampsia effects between 4-8% of all pregnancies and is a major cause of maternal mortality, contributing to 20% of maternal deaths in the United States. To date there is no treatment or method of prevention for placenta insufficiency or preeclampsia except for premature delivery of the fetus. One major barrier that remains is that despite years of research we do not have a diagnostic, pre-symptomatic biomarker to identify women at risk for preeclampsia or other trophoblast related placental disorders. This proposal will investigate a novel gene regulatory mechanism, LIN28, in trophoblast cells to determine if disrupted regulation produces defective placentation and poor trophoblast invasion. Identifying the role of LIN28 gene regulatory mechanisms holds promise towards identifying markers that may be used to predict poor placental development. This proposal will test the hypothesis that the pluripotency factor LIN28 regulates molecular pathways controlling proliferation and invasion of human trophoblast cells by completing the following three aims.
Aim 1) Determine how LIN28 regulates proliferation and invasion of human extravillous trophoblast (EVT) cells.
This aim will use targeted degradation or gain-of-function of LIN28 in first trimester human trophoblast cell lines to investigate the functional mechanism of LIN28 in trophoblast cells.
Aim 2) Determine if LIN28 is necessary for the establishment and maintenance of the placenta.
This aim will create an animal model of trophoblast-specific degradation and gain-of-function of mouse Lin28 to investigate the functional role of Lin28 in an in vivo animal model.
Aim 3) Determine how let-7 miRNA content in exosomes released from human EVT cells is controlled by LIN28.
This aim will test how LIN28 regulates miRNA content in human EVT cell secreted exosomes, a potential biomarker of placental disorders. Long-term the goal of this research is to identify critical genes involved in healthy and pathologic placental development and identify markers that are useful for pre- symptomatic diagnosis of placental abnormalities.
Disrupted trophoblast cell proliferation, differentiation and invasion are major factors contributing to loss of pregnancy and placental pathologies including preeclampsia and placental insufficiency resulting in fetal intrauterine growth restriction (IUGR). Preeclampsia effects between 4-8% of all pregnancies worldwide and accounts for 20% of maternal mortality in the United States. This research will improve our knowledge of trophoblast proliferation, differentiation and invasion, by investigating LIN28, a novel gene regulatory pathway in trophoblast cells, with the long-term goal of identifying biomarkers of placental disease.
|Seabrook, Jill L; Cantlon, Jeremy D; Cooney, Austin J et al. (2013) Role of LIN28A in mouse and human trophoblast cell differentiation. Biol Reprod 89:95|