Histone Demethylases and Trophoblast Differentiationt

组蛋白去甲基化酶和滋养层分化

基本信息

批准号：
10459451
负责人：
Soumen Paul
金额：
$ 43.07万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459451
关键词：
ASCL2 gene Adult Adverse effects Cell Lineage Cells Chorion Conceptus Cone Defect Development Disease Ectoderm Embryo Ensure Epigenetic Process Fetal Growth Retardation Functional disorder GCM1 gene Gene Expression Genetic Transcription Glycogen Histones Human Impairment Infant Health KDM1A gene Labyrinth Lead Maintenance Maternal Health Maternal-Fetal Exchange Mediating Molecular Mus PRDM1 gene Parietal Pathogenesis Pathologic Pathway interactions Placenta Placentation Population Pre-Eclampsia Pregnancy Pregnancy loss Premature Birth Process Public Health Reproduction Research Role Spiral Artery of the Endometrium Syncytiotrophoblast TACSTD1 gene Testing blastocyst conditional knockout cytotrophoblast early pregnancy loss fetal histone demethylase implantation insight mouse model mutant mouse model natural Blastocyst Implantation postnatal premature prevent progenitor programs self-renewal stem-like cell trophoblast trophoblast stem cell

项目摘要

Abstract Placental dysfunction leads to pregnancy-associated disorders, including intrauterine growth restriction (IUGR) and preeclampsia, and also serves as a developmental cause for postnatal and adult diseases. Often, the causal alterations in the placentation process, which lead to defective pregnancies, occur early in gestation. Defective development and differentiation of trophoblast progenitors are leading causes for pathological pregnancies. However, we have a poor understanding of molecular mechanisms that regulate trophoblast progenitor self-renewal, differentiation and function in postimplantation embryos. Studies on mutant mouse models and mouse trophoblast stem cells (mouse TSCs) implicated lysine-specific demethylase 1 (LSD1), the first identified histone demethylas, as a critical regulator to prevent premature differentiation of mouse TSCs. However, the importance of LSD1 in the context of differentiated trophoblast cells of a matured placenta is yet to be defined. Also, the importance of LSD1 in human trophoblast development has never been tested. Our preliminary findings establish that LSD1 expression is conserved in trophoblast progenitors across mammalian species, including humans. Thus, in this proposal we will investigate importance of LSD1 in the development of specialized trophoblast cells, namely syncytiotrophoblasts (SynTBs) and invasive trophoblasts, at the maternal- fetal interface. We will also define importance of LSD1 in human trophoblast differentiation and interrogate LSD1 function. Two specific aims are proposed. Aim 1 will study Lsd1 conditional knockout mouse model to test the hypothesis that cell-autonomous function of LSD1 in lineage-specific trophoblast progenitors ensures establishment of differentiated SynTBs and invasive trophoblast cells at the maternal-fetal interface. In Aim 2, using CTB-derived human trophoblast stem cells, we will test the hypothesis that LSD1 establishes a conserved gene expression program in mouse and human trophoblast progenitors and impairment of LSD1-dependent transcriptional program will impair self-renewal and differentiation potential of human trophoblast progenitors. In addition, we will also interrogate significance of LSD1-dependent mechanisms in the context of pathological pregnancies.

抽象的胎盘功能障碍会导致妊娠相关疾病，包括宫内生长受限（IUGR）和先兆子痫，也是产后和成人疾病的发育原因。经常，导致妊娠缺陷的胎盘过程的因果变化发生在早期妊娠。滋养层祖细胞的发育和分化缺陷是导致这些问题的主要原因病理性妊娠。然而，我们对调节的分子机制了解甚少。滋养层祖细胞在植入后胚胎中的自我更新、分化和功能。研究突变小鼠模型和小鼠滋养层干细胞（小鼠 TSC）涉及赖氨酸特异性去甲基化酶 1 (LSD1)，第一个确定的组蛋白去甲基化，作为防止小鼠过早分化的关键调节因子 TSC。然而，LSD1 在成熟胎盘的分化滋养层细胞中的重要性是尚待定义。此外，LSD1 在人类滋养层发育中的重要性从未得到测试。我们的初步研究结果表明，LSD1 表达在哺乳动物的滋养层祖细胞中是保守的物种，包括人类。因此，在本提案中，我们将研究 LSD1 在开发中的重要性专门的滋养层细胞，即合体滋养层细胞（SynTB）和侵袭性滋养层细胞，位于母体胎儿接口。我们还将定义 LSD1 在人类滋养层分化中的重要性并询问 LSD1 功能。提出了两个具体目标。目标1将研究Lsd1条件敲除小鼠模型来测试假设谱系特异性滋养层祖细胞中 LSD1 的细胞自主功能确保在母胎界面建立分化的 SynTB 和侵袭性滋养层细胞。在目标 2 中，我们将使用 CTB 衍生的人滋养层干细胞来检验 LSD1 的假设在小鼠和人类滋养层祖细胞和损伤中建立保守的基因表达程序 LSD1依赖性转录程序的缺失将损害人类的自我更新和分化潜力滋养层祖细胞。此外，我们还将探讨 LSD1 依赖性机制在病理性妊娠的背景。