Role of MTA3 in trophoblast function and placental development

描述(申请人提供)：滋养层功能受损与子痫前期(PE)的发展直接相关。因此，了解滋养层细胞分化和功能的基因调控机制，将有助于揭示PE的发病机制，为临床提供更有效的治疗干预措施，提高我们对胎盘功能的整体认识。染色质重塑蛋白在胚胎发育的基因调控中发挥重要作用。该提案的总体目标将是研究染色质重塑蛋白--转移相关蛋白3(MTA3)在滋养层细胞分化、功能及其与PE的临床相关性中的作用。MTA3是核小体染色质重塑和去乙酰化复合体(NuRD)的重要组成部分，在乳腺癌细胞中高表达，已被证明在细胞增殖、分化和侵袭中发挥重要作用。MTA3在胎盘滋养层细胞中也有高表达，但其在滋养层细胞中的功能仍不清楚。我们的主要假设是，MTA3是调节胎盘滋养层细胞融合和侵袭的基因正确表达所必需的，MTA3失调可能参与PE的病理过程。在特定的目标1中，我们将确定MTA3在胎盘滋养层细胞融合中的作用及其作用 体育病理学专业。在特定的目标2中，我们将确定MTA3在滋养层侵袭中的作用，以及它在PE病理中的作用。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调控滋养细胞分化和功能的表观遗传学机制(S)的理解，以及它们在PE发病机制中的作用。

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.