Small RNAs at the placental maternal communication interface

描述（由申请人提供）：我们的长期研究目标是通过支持每个胎儿实现其先天生长潜力来改善妊娠结局和新生儿健康。在这个探索性的建议中，我们部署了一个新的研究计划，该计划以控制胎盘-母体通信的表观基因组信号为中心。我们认为microRNA和其他小RNA信号在调节胎盘和母体基因表达，从而成功妊娠中具有非凡的意义。与DNA甲基化、组蛋白修饰或核小体重塑的变化不同，miRNA和其他小RNA直接调节mRNA和蛋白质的表达。虽然普遍存在于每个组织中，并能够调节不同的发育，生理和病理过程，但大多数miRNA的功能仍然未知。胎盘在半同种异体移植胎儿和母体宿主之间具有独特的界面。重要的是，人类胎盘表达独特的miRNA种类，这些种类通常不存在于其他地方。我们组建了一个跨学科的团队，涵盖了发育，计算生物学和病理学方面的专业知识，共同的目标是阐明microRNA和小RNA在母亲和胎儿胎盘单位之间的相互作用中的作用。在已经确定了正常和缺氧条件下原代人滋养层中的差异microRNA表达及其独特功能之后，我们现在寻求使用下一代深度测序技术来全面询问人母体血液和胎盘中的microRNA和小RNA种类，并部署新的计算工具来分析正常妊娠或妊娠并发症中microRNA和小RNA表达的动态变化。临床相关的胎盘损伤。我们将专门评估组装在囊泡纳米颗粒（外泌体）中的小RNA的性质，这些小RNA可能在母亲和胎儿胎盘单位之间运输。从我们的数据中收集的信息不仅可以阐明影响人类胚胎发育的非编码RNA途径，还可以提出新的临床相关信号，旨在告知胎盘损伤和低于标准妊娠结局的风险。 公共卫生相关性：我们分析妊娠特异性RNA分子，这些分子是胎盘基因表达的关键调节因子。在这个项目中，我们评估了这些小RNA在胎儿胎盘单位和母亲之间的通信中的作用。我们的研究结果将揭示胎盘和母体RNA的独特作用，从而为胎盘功能障碍引起的产科疾病提供新的线索，这些疾病影响全国每年400万分娩中的5-10%。

DESCRIPTION (provided by applicant): Our long-term research goal is to improve pregnancy outcome and newborn health by supporting each fetus in attaining its innate growth potential. In this exploratory proposal, we deploy a novel research plan that centers on epigenomic signals that control placenta-maternal communication. We posit that microRNA and other small RNA signals have an extraordinary significance in regulation of placental and maternal gene expression and consequently, successful pregnancy. Unlike changes in DNA methylation, histone modifications or nucleosomal remodeling, miRNAs and other small RNAs directly modulate the expression of mRNAs and proteins. While prevalent in every tissue and capable of modulating diverse developmental, physiological and pathological processes, the function of most miRNA remains unknown. The placenta distinctively interfaces between the semi-allograft fetus and the maternal host. Importantly, the human placenta expresses unique miRNA species that are not normally present elsewhere. We have assembled a trans-disciplinary team that spans expertise in development, computational biology, and pathology, sharing the common goal of elucidating the role of microRNAs and small RNAs in the cross talk between the mother and the feto-placental unit. Having already defined differential microRNA expression and their unique function in primary human trophoblasts in normal and hypoxic conditions, we now seek to use next generation deep sequencing technology to comprehensively interrogate microRNA and small RNA species in the human maternal blood and the placenta, and deploy novel computational tools to analyze dynamic changes in microRNA and small RNA expression in normal pregnancies or pregnancies complicated by clinically relevant placental injury. We will specifically assess the nature of small RNAs assembled in vesicular nano-particles (exosomes), which may traffic small RNAs between the mother and the feto-placental unit. Information gleaned from our data may not only illuminate non-coding RNA pathways that influence human embryonic development, but may also suggest new, clinically-relevant signals, designed to inform the risk of placental injury and sub-standard pregnancy outcome. PUBLIC HEALTH RELEVANCE: We analyze pregnancy-specific RNA molecules that are key regulators of placental gene expression. In this project we assess the role of these small RNAs in communication between the feto-placental unit and the mother. Results from our study will uncover a unique role of placental and maternal RNAs, and thus shed new light on obstetrical diseases stemming from placental dysfunction, which affect 5-10% of the annual four million deliveries nationwide.