Stem Cells and Epigenetics of Trophoblast Lineage Development

描述（由申请人提供）：妊娠的建立取决于母体和胚胎结构之间精确对话的执行。母胚交流的环境是在子宫内。胚胎在子宫内的存活、生长和发育取决于胚胎表面上的特化细胞群的发育。这些细胞是滋养层谱系的最早组成部分，并且具有进一步分化为具有将母体环境转化为适于胚胎发育的适宜位点的能力的细胞的独特能力，包括重建母体脉管系统以促进营养流和获得有效的营养素运输到胎儿。滋养层细胞系的适当发育对于妊娠的建立是必不可少的。滋养层细胞谱系决定、扩增和分化的破坏是早期妊娠丢失的核心。我们假设这些基本细胞过程的调节是发现早期妊娠丢失病因的关键。因此，我们必须扩大我们的了解控制滋养层细胞谱系的发展的分子机制。拟议的计划工作包括三个研究项目，旨在阐明调节滋养层细胞谱系发育的分子机制。重点是转录和表观遗传机制（转录因子，组蛋白修饰，染色质组织者）控制干细胞群体。研究项目I评估了TEAD 4在滋养层谱系调节中的作用;研究项目II评估了SATB蛋白对滋养层干细胞干细胞状态维持的贡献;研究项目III调查了组蛋白H3 K9甲基化在滋养层谱系发育调节中的参与。该实验利用啮齿动物干细胞体外和体内模型，啮齿动物早期胚胎操作，以及转录和表观遗传分析中不同方法的分类，并将通过具有成本效益的管理和研究核心的可用性来促进。拟议的方案工作具有高度互动性，并受益于每个参与者的独特专长。

DESCRIPTION (provided by applicant): The establishment of pregnancy is dependent upon the execution of a precise dialog between maternal and embryonic structures. The setting for the maternal-embryonic communication is within the uterus. Embryonic survival, growth, and development within the uterus are dependent upon development of a specialized population of cells on the surface of the embryo. These cells are the earliest constituents of the trophoblast lineage and have the unique capacity to further differentiate into cells with the ability to conver the maternal environment into a hospitable site for embryonic development, including restructuring maternal vasculature to facilitate nutrient flow and acquisition of efficient nutrien transport to the fetus. Appropriate development of the trophoblast lineage is essential for the establishment of pregnancy. Disruptions in trophoblast lineage determination, expansion, and differentiation are at the core of early pregnancy loss. We hypothesize that the regulation of these fundamental cellular processes is a key to discovering the etiology of early pregnancy loss. Consequently, it is imperative that we expand our understanding of molecular mechanisms controlling development of the trophoblast lineage. The proposed programmatic effort consists of three research projects directed toward elucidating molecular mechanisms regulating trophoblast lineage development. The emphasis is on transcriptional and epigenetic mechanisms (transcription factor, histone modifications, chromatin organizer) controlling stem cell populations. RESEARCH PROJECT I evaluates the role of TEAD4 in the regulation of the trophoblast lineage; RESEARCH PROJECT II assesses the contributions of SATB proteins to the maintenance of the trophoblast stem cell stem state; RESEARCH PROJECT III investigates the involvement of histone H3K9 methylation in the regulation of trophoblast lineage development. The experimentation utilizes rodent stem cell in vitro and in vivo models, early embryo manipulation in rodents, and assortment of different methodologies in transcriptional and epigenetic analysis and will be facilitated by the availability of cost-effective administrativ and research cores. The proposed programmatic effort is highly interactive and benefits from the unique expertise of each participant.