The Role of MicroRNA in Placental Differentiation

描述(申请人提供)：一套精确和良好协调的分子和细胞信号管理卢曼胎盘的分化和功能。人类胎盘的滋养层双层位于胎盘绒毛表面，能够执行一系列对胎盘新陈代谢至关重要的功能，从而促进胎儿发育。虽然最近的研究阐明了在小鼠、绵羊和人类胎盘中影响滋养层基因转录调控的空间和时间路径，但对于这些信号在维持滋养层时间平衡和胎盘对损伤的适应方面的整合知之甚少。五年前几乎还不为人所知的是，microRNAs(MiRNAs)在从蠕虫到人类的各种生物的组织中普遍表达。作为内源性RNA沉默机制的一部分，这些短链RNA与RNA干扰沉默复合体协同作用，降解靶转录和沉默翻译，从而调节发育和维持体内平衡。此外，miRNA表达异常与人类疾病有关。我们和其他人最近发现，小鼠和人类胎盘都表达miRNAs，但它们的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础作用，以及胎盘功能障碍的深远后果，研究miRNAs在这一器官中的功能是至关重要的。这一探索性的翻译研究项目将最近发现的miRNA途径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。在这项拟议的工作中，我们将检验这一假设，即离散的miRNA物种在人类滋养层细胞中表达，并调节正常的胎盘功能以及对缺氧损伤的适应性反应。从我们的研究中收集的信息可能有助于阐明控制滋养层细胞对损伤的适应性反应的新机制，并揭示内源性RNAi在人类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.