Role of MTA3 in trophoblast function and placental development

描述（由申请人提供）：滋养层功能受损与先兆子痫（PE）的发生直接相关。因此，了解滋养细胞分化和功能的基因调控机制，将揭示PE的发病机制，这可能会导致更有效的治疗干预措施，以及提高我们对胎盘功能的全面了解。染色质重塑蛋白在胚胎发育过程中的基因调控中起着关键作用。本提案的总体目标是研究染色质重塑蛋白，转移相关蛋白3（MTA 3）在滋养层分化，功能及其与PE的临床相关性中的作用。MTA 3是核小体染色质重塑和脱乙酰化复合物（NuRD）的重要组分，并且在乳腺癌细胞中高度表达，其中已显示其在细胞增殖、分化和侵袭中起重要作用。MTA 3在胎盘滋养层细胞中也高度表达;然而，其在滋养层细胞中的功能在很大程度上仍然未知。我们的总体假设是，MTA 3是调节胎盘滋养层细胞融合和侵袭的基因的适当表达所必需的，并且MTA 3失调可能有助于PE的病理学。在特定目标1中，我们将确定MTA 3在胎盘滋养层融合中的作用，以及其在胎盘滋养层融合中的作用。 体育病理学在特定目标2中，我们将确定MTA 3在滋养层细胞侵袭中的作用，以及其在PE病理学中的作用。为了解决这些问题，我们将使用分子，细胞和生化分析。这些研究将加深我们对滋养细胞分化和功能的表观遗传机制及其在PE发病机制中的作用的理解。

DESCRIPTION (provided by applicant): 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.