The Role of MicroRNA in Placental Differentiation

描述（由申请人提供）：一组精确且精心编排的分子和细胞信号控制着人胎盘的分化和功能。人类胎盘的滋养细胞双分子层位于胎盘绒毛表面，能够很好地执行一系列对胎盘代谢至关重要的功能，从而促进胎儿发育。尽管最近的研究揭示了影响小鼠、绵羊和人类胎盘中滋养层基因转录调控的空间和时间途径，但对于这些信号在滋养层维持平衡和胎盘对损伤的适应中的整合却知之甚少。microRNAs （miRNAs）在从蠕虫到人类的各种生物组织中普遍表达，这在五年前几乎不为人所知。作为内源性RNA沉默机制的一部分，这些短RNA链与RNA干扰沉默复合物协同作用，降解靶转录物并沉默翻译，从而调节发育和维持体内平衡。此外，miRNA表达失调与人类疾病有关。我们和其他人最近表明，小鼠和人类胎盘都表达miRNAs，但其表达模式和功能尚不清楚。考虑到胎盘在哺乳动物胚胎发育中的基本作用，以及胎盘功能障碍的深远影响，研究mirna在该器官中的功能至关重要。这个探索性的转化研究项目，将最近发现的miRNA通路与人类滋养细胞生物学和疾病联系起来，符合R21的资助目标。在我们提出的工作中，我们将验证在人类滋养细胞中表达离散miRNA物种并调节正常胎盘功能以及对缺氧损伤的适应性反应的假设。从我们的研究中收集到的信息可能会揭示滋养细胞对损伤适应性反应的新机制，并揭示内源性RNAi在人胎盘分化和功能中的作用。

DESCRIPTION (provided by applicant): A precise and well-orchestrated set of molecular and cellular signals governs the differentiation and function of the luman placenta. Surfacing the placental villi, the trophoblast bilayer of the human placenta is well positioned to execute a series of functions that are essential for placental metabolism, and consequently facilitate fetal development. Whereas recent studies illuminated spatial and temporal pathways that influence transcriptional regulation of trophoblast genes in mouse, sheep and human placentas, little is known about the integration of these signals into maintenance of trophoblast tiomeostasis and placental adaptation to injury. Practically unknown five years ago, microRNAs (miRNAs) are ubiquitously expressed in tissues of diverse organisms, from worms to humans. As a part of the endogenous RNA silencing machinery, these short RNA strands act in concert with the RNA interference silencing complex to degrade target transcripts and silence translation, and thereby regulate development and maintain homeostasis. Moreover, dysregulated miRNA expression has been implicated in human diseases. We and others have recently shown that both the mouse and human placentas express miRNAs, yet their pattern of expression and function are unknown. Considering the fundamental role of the placenta in development of the mammalian embryo, as well as the profound consequences of placental dysfunction, it is paramount to investigate the function of miRNAs in this organ. This exploratory translational research project, which bridges recently discovered miRNA pathways to human trophoblast biology and disease, matches the R21 funding objectives. In the proposed work we will test the hypothesis that discrete miRNA species are expressed in human trophoblasts and regulate normal placental function as well as adaptive response to hypoxic injury. Information gleaned from our studies will likely shed light on novel mechanisms that govern trophoblast adaptive response to injury, and uncover the role of endogenous RNAi in the differentiation and function of the human placenta.