Histone Demethylases and Trophoblast Differentiationt

组蛋白去甲基化酶和滋养层分化

• 批准号: 10239804
• 负责人: Soumen Paul
• 金额: $ 42.82万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 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/10239804
• 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

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 胎盘功能障碍导致妊娠相关疾病，包括宫内生长限制 （IUGR）和先兆子痫，也是产后和成人疾病的发展原因。经常， 胎盘过程中导致怀孕缺陷的因果改变发生在早期 妊娠。滋养细胞祖细胞的发展和分化是主要原因 病理怀孕。但是，我们对调节分子机制的理解很差 滋养细胞祖细胞自我更新，植入后胚胎中的分化和功能。研究 突变小鼠模型和小鼠滋养细胞干细胞（小鼠TSC）涉及赖氨酸特异性脱甲基酶1 （LSD1），第一个确定的组蛋白脱甲基，是防止小鼠过早分化的关键调节剂 TSC。但是，在成熟胎盘的分化滋养细胞细胞的背景下，LSD1的重要性是 尚待定义。同样，LSD1在人类滋养细胞发育中的重要性从未进行过测试。我们的 初步发现表明，LSD1表达在跨哺乳动物的滋养细胞祖细胞中保守 物种，包括人类。因此，在此提案中，我们将调查LSD1在发展中的重要性 在母体 - 胎儿界面。我们还将定义LSD1在人类滋养细胞分化和询问LSD1中的重要性 功能。 提出了两个具体目标。 AIM 1将研究LSD1条件敲除鼠标模型以测试 假设LSD1在谱系特异性滋养细胞祖细胞中的细胞自主功能可确保 在母亲界面上建立分化的征服和侵入性滋养细胞细胞。 在AIM 2中，使用CTB来源的人滋养细胞干细胞，我们将测试LSD1的假设 在小鼠和人类滋养细胞祖细胞和损害中建立一个保守的基因表达程序 LSD1依赖性转录程序的损害将损害人类的自我更新和差异潜力 滋养细胞祖细胞。此外，我们还将询问LSD1依赖机制的意义 病理怀孕的背景。