Role of MTA3 in trophoblast function and placental development

MTA3 在滋养层功能和胎盘发育中的作用

基本信息

批准号：
8919934
负责人：
Kai Wang
金额：
$ 7.48万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8919934
关键词：
Address Affect Biochemical Biological Assay Breast Cancer Cell CDH1 gene Cell Line Cell Lineage Cell Maintenance Cell Proliferation Cells Cessation of life Complex Development Disease Duct (organ) structure Early Diagnosis Embryo Embryonic Development Epigenetic Process Epithelial Gene Expression Gene Expression Regulation Genes Goals Health Human Human Chorionic Gonadotropin Knowledge Laboratories Lead Link MMP2 gene MMP9 gene Mammary gland Mediating Messenger RNA Methods Molecular Mus Names Neoplasm Metastasis Nucleosomes Pathogenesis Pathology Placenta Placentation Play Pre-Eclampsia Pregnancy Pregnancy Complications Proteins RNA Interference Regulation Research Role Sampling Stem cells Termination of pregnancy Therapeutic Intervention United States Villous Work base blastocyst cell type chromatin remodeling clinically relevant clinically significant epigenetic regulation fetal improved knock-down pluripotency trophoblast

项目摘要

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.

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，了解滋养层分化和功能中的基因调控机制将揭示PE的发病机制，从而可能导致更有效的治疗干预，并增强我们对胎盘功能的整体了解。染色质重塑蛋白在胚胎发育过程中的基因调控中发挥着关键作用。该提案的总体目标是研究染色质重塑蛋白、转移相关蛋白 3 (MTA3) 在滋养层分化、功能中的作用及其与 PE 的临床相关性。 MTA3是核小体染色质重塑和脱乙酰复合物（NuRD）的重要组成部分，在乳腺癌细胞中高表达，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高表达；然而，其在滋养细胞中的功能仍然很大程度上未知。我们的总体假设是，调节胎盘滋养层融合和侵袭的基因的正确表达需要 MTA3，并且 MTA3 失调可能导致 PE 的病理学。在具体目标1中，我们将确定MTA3在胎盘滋养层融合中的作用，及其作用在PE病理学中。在具体目标 2 中，我们将确定 MTA3 在滋养层侵袭中的作用及其在 PE 病理学中的作用。为了解决这些问题，我们将使用分子、细胞和生化检测。拟议的研究将增强我们对调节滋养层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。