RESEARCH PROJECT II: SATB Regulation of the Trophoblast Stem Cell State

研究项目 II：SATB 对滋养层干细胞状态的调节

• 批准号: 8743038
• 负责人: Mohammad A.K. Rumi
• 金额: $ 28.57万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-24 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743038
• 关键词: AT Rich Sequence; Binding Proteins; Cell model; Cells; Chromatin; Communication; Complex; Coupled; Development; Developmental Gene; Disease; Embryo; Embryonic Development; Environment; Epigenetic Process; Failure; Gene Expression; Gene Expression Profile; Growth; Homeodomain Proteins; In Vitro; Investigation; Lead; Maintenance; Modification; Mus; Mutagenesis; Pathway interactions; Play; Population; Positioning Attribute; Pregnancy; Pregnancy Maintenance; Pregnancy loss; Process; Property; Proteins; Regulation; Research; Research Project Grants; Rodent; Role; Signal Pathway; Site; Stem cells; Uterus; abstracting; genome wide association study; genome-wide analysis; human disease; human stem cells; improved; in vivo; insight; multipotent cell; mutant mouse model; natural Blastocyst Implantation; novel; self-renewal; stem; trophoblast

PROJECT SUMMARY/ABSTRACT (RESEARCH PROJECT II) The trophoblast lineage arises early in embryonic development through a complex interaction of transcriptional and epigenetic regulators controlling key signaling pathways. Trophoblast stem (TS) cells possess the capacity to self-renew and differentiate into specialized trophoblast cell populations required for the establishment and maintenance of pregnancy. However, the epigenetic modifications, and the hierarchy of the transcriptional regulators, which determine trophoblast lineage, maintain the trophoblast cell stem state and regulate the multilineage differentiation are poorly understood. We have identified two related proteins, special AT-rich sequence-binding protein 1 (SATB1) and SATB2, which can act as chromatin organizers and transcriptional regulators, contribute to both the maintenance and expansion of TS cells and the inhibition of trophoblast differentiation. SATB proteins are proposed to play a key role in the regulatory network controlling trophoblast development. In this research project, three specific aims are proposed: 1) to investigate the role of SATB proteins in the regulation of trophoblast lineage determination; 2) to establish the position of SATB proteins in the hierarchy of regulators controlling the TS cell stem state; 3) to evaluate the in vivo role of SATB proteins in trophoblast development. The proposed study will utilize in vitro rodent and human stem cell models and mouse mutagenesis to explore the role of SATB proteins in regulating the trophoblast development. Genome wide analysis of transcriptional and epigenetic modifications will be coupled to transcriptome analysis to identify upstream regulators of SATB expression and downstream targets of SATB action. This research investigation will reveal novel properties of trophoblast stem cell regulation and expand our understanding of the disorders associated with early pregnancy loss.

项目摘要/摘要（研究项目 II） 滋养层谱系在胚胎发育早期通过转录因子的复杂相互作用而出现。 和控制关键信号通路的表观遗传调节因子。滋养层干细胞 (TS) 具有以下能力 自我更新并分化为建立和维持所需的专门滋养层细胞群 维持妊娠。然而，表观遗传修饰和转录的层次结构 调节因子，决定滋养层谱系，维持滋养层细胞干状态并调节 人们对多谱系分化知之甚少。我们已经鉴定出两种相关的蛋白质，特别是富含 AT 的蛋白质 序列结合蛋白 1 (SATB1) 和 SATB2，可充当染色质组织者和转录 调节因子，有助于 TS 细胞的维持和扩增以及滋养层细胞的抑制 差异化。 SATB 蛋白被认为在控制滋养层的调控网络中发挥关键作用 发展。在这个研究项目中，提出了三个具体目标：1）研究 SATB 的作用 调节滋养层谱系测定的蛋白质； 2) 确定 SATB 蛋白在 控制 TS 细胞干状态的调节器的层次结构； 3）评估SATB蛋白在体内的作用 滋养层发育。拟议的研究将利用体外啮齿动物和人类干细胞模型 小鼠诱变探索 SATB 蛋白在调节滋养层发育中的作用。基因组 转录和表观遗传修饰的广泛分析将与转录组分析相结合，以 确定 SATB 表达的上游调节因子和 SATB 作用的下游目标。这项研究 研究将揭示滋养层干细胞调节的新特性并扩大我们的理解 与早孕流产相关的疾病。