Placental injury and microRNA

描述(申请人提供)：我们的首要目标是了解人类胎盘滋养层细胞在妊娠后期的分化过程，以及滋养层细胞对损伤的适应性反应。滋养细胞分化异常和胎盘功能障碍的临床后果是深远的，通常会导致胎儿宫内死亡或胎儿生长受限。在这些侮辱中幸存下来的新生儿将面临终身并发症的风险，包括神经发育障碍和成人代谢综合征的更高发病率。虽然这些情况与胎盘功能障碍的关系已经得到了严格的证实，但滋养层细胞分化和对损伤的适应的机制却知之甚少，也没有得到足够的研究。反映出我们对胎儿生长受限的病理生理学缺乏了解，目前还没有有效的治疗方法。防止胎儿进一步损伤的唯一干预措施是分娩，这是为了防止进一步损伤，但通常会导致早产。最近发现的microRNA(MiRNA)为细胞特异性转录和蛋白质表达的调控增加了一个新的维度。我们对内源性miRNA的表达及其在哺乳动物组织发育和功能中的作用的了解是初步的。具体地说，关于胎盘miRNA的信息很少。从目前对其他组织的研究中收集的信息，以及我们自己最近的数据，支持了我们的假设，即不同类型的人胎盘miRNA的表达和功能控制着滋养层细胞的分化和对损伤的适应。在我们初步数据的基础上，我们将从机械上破译滋养层细胞对损伤适应过程中调节的miRNAs的作用。通过这些分析，我们试图改变我们对人类妊娠后半期滋养细胞功能障碍的理解，并探索先前未知的滋养细胞损伤反应途径。我们的建议是独一无二的，因为(A)我们专注于迄今为止在胎盘中尚未被探究的基因调控的新途径，(B)我们计划进行的研究建立在高通量miRNA-微阵列分析的公正、尖端技术的基础上，结合全面的mRNA阵列和蛋白质组学，旨在确定胎盘中相关的miRNA靶标以及这些miRNA的调控功能，以及(C)我们利用创新工具来建立“因果”关系，而不仅仅是关联。我们的数据不仅将阐明滋养细胞对损伤的适应的分子基础，而且也可能为未来对妊娠合并胎盘功能障碍的妇女进行新的诊断和治疗方法的翻译研究奠定基础。 公共卫生相关性：作为发育中胚胎氧气和营养的“唯一来源”提供者，胎盘对胎儿发育是必不可少的。我们的研究旨在阐明胎盘短RNA分子(MicroRNAs)在胎盘对外界侮辱的适应中的作用。我们的实验将扩大我们对胎盘疾病的理解，从而阐明胎儿和新生儿疾病的起源及其后遗症。

DESCRIPTION (provided by applicant): Our overarching goal is to understand the process of human placental trophoblast differentiation during the latter half of pregnancy, and the adaptive response of trophoblasts to injury. The clinical consequences of abnormal trophoblast differentiation and placental dysfunction are far-reaching, typically leading to intrauterine fetal death or fetal growth restriction. Newborns surviving these insults are at risk for lifelong complications, including neuro-developmental dysfunction and a greater incidence of the adult metabolic syndrome. Whereas the association of these conditions with placental dysfunction has been scrupulously substantiated, the mechanisms underlying trophoblast differentiation and adaptation to injury are poorly understood and insufficiently explored. Reflecting our poor understanding of the pathophysiology of fetal growth restriction, there is no effective treatment for this condition. The only intervention to prevent further fetal damage is delivery, which is designed to prevent further injury, yet commonly leads to prematurity. The recent discovery of microRNA (miRNA) adds a new dimension to cell-specific regulation of transcript and protein expression. Our knowledge of endogenous miRNA expression and its role in the development and function of mammalian tissues is rudimentary. Specifically, information regarding placental miRNA is scarce. Information gleaned from current studies in other tissues, bolstered by our own recent data, supports our hypothesis that the expression and function of discrete types of human placental miRNA govern trophoblast differentiation and adaptation to injury. Building on our preliminary data, we will mechanistically decipher the action of miRNAs that are regulated during trophoblast adaptation to injury. Through these analyses we seek to transform our understanding of trophoblast dysfunction during the second half of human pregnancy, and explore previously unknown pathways in trophoblast response to injury. Our proposal is unique, because (a) we focus on novel pathways of gene regulation that have not been interrogated thus far in the placenta, (b) we build our planned investigation on an unbiased, cutting edge technology in high-throughput miRNA-microarray analysis, combined with comprehensive mRNA arrays and proteomics, designed to define relevant miRNA targets in the placenta, and the regulatory function of these miRNA, and (c) we utilize innovative tools to establish a "cause and effect" relationship, not mere associations. Our data will not only illuminate the molecular underpinning of trophoblast adaptation to injury, but may also lay the foundation to future translational research into novel diagnostic and therapeutic approaches for women with pregnancies complicated by placental dysfunction. PUBLIC HEALTH RELEVANCE: As a "sole-source" provider of oxygen and nutrients to the developing embryo, the placenta is essential to fetal development. Our research is designed to elucidate the action of placental short RNA molecules (microRNAs) in adaptation of the placenta to external insults. Our experiments will broaden our understanding of placental diseases, and therefore illuminate origins of fetal and neonatal diseases, and their sequelae.