Compromised trophoblast function is directly linked to the development of Preeclampsia (PE). Therefore, understanding the mechanism of gene regulation in trophoblast differentiation and function will reveal the pathogenesis of PE, which may lead to more effective therapeutic interventions as well as enhance our overall understanding of placental function. Chromatin remodeling proteins play critical roles in gene regulation during embryo development. The overall goal of this proposal will be to investigate the role of the chromatin remodeling protein, Metastasis-Associated Protein 3 (MTA3), in trophoblast differentiation, function and its clinical relevance with PE. MTA3 is an important component of the nucleosome chromatin remodeling and deacetylating complex (NuRD), and is highly expressed in breast cancer cells, where it has been shown to play an important role in cell proliferation, differentiation and invasion. MTA3 is also highly expressed in placental trophoblasts;however, its function in trophoblasts is still largely unknown. Our overarching hypothesis is that MTA3 is required for proper expression of genes that regulate placental trophoblast fusion and invasion, and MTA3 dysregulation can contribute to the pathology of PE.
In Specific Aim 1, we will determine the role of MTA3 in placental trophoblast fusion, and its role in PE pathology.
In Specific Aim 2, we will determine the role of MTA3 in trophoblast invasion, and its role in PE pathology. To address these questions, we will use molecular, cellular, and biochemical assays. The proposed studies will enhance our understanding of the epigenetic mechanism(s) that regulate trophoblast differentiation and function and their role in the pathogenesis of PE.
In the long run the proposed studies will expand our understanding of epigenetic regulation of placenta development, especially the role of MTA3 gene (chromatin remodeling protein) in the pathogenesis of Preeclampsia. These results will lead to better methods for early diagnosis/cure of Preeclampsia.