Placental injury and microRNA

描述（由申请人提供）：我们的首要目标是了解妊娠后半期人类胎盘滋养层分化的过程，以及滋养层对损伤的适应性反应。异常滋养层分化和胎盘功能障碍的临床后果是深远的，通常导致宫内胎儿死亡或胎儿生长受限。幸存下来的新生儿有终身并发症的风险，包括神经发育功能障碍和成人代谢综合征的发病率更高。虽然这些条件与胎盘功能障碍的关联已被严格证实，滋养层细胞分化和适应损伤的机制知之甚少，探索不够。反映了我们对胎儿生长受限的病理生理学的认识不足，这种情况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，其目的是防止进一步损伤，但通常会导致早产。最近发现的microRNA（miRNA）为转录和蛋白质表达的细胞特异性调控增加了新的维度。我们对内源性miRNA表达及其在哺乳动物组织发育和功能中的作用的了解是基本的。具体而言，关于胎盘miRNA的信息很少。从其他组织的当前研究中收集的信息，由我们自己最近的数据支持，支持我们的假设，即人类胎盘miRNA的离散类型的表达和功能控制滋养层分化和对损伤的适应。基于我们的初步数据，我们将机械地破译在滋养层适应损伤过程中调控的miRNA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层功能障碍的理解，并探索滋养层对损伤的反应中以前未知的途径。我们的建议是独特的，因为（a）我们专注于迄今为止尚未在胎盘中询问的新的基因调控途径，（B）我们将我们计划的研究建立在高通量miRNA微阵列分析中的无偏见的尖端技术上，结合全面的mRNA阵列和蛋白质组学，旨在定义胎盘中的相关miRNA靶点，以及这些miRNA的调控功能，以及（c）我们利用创新工具建立“因果”关系，而不仅仅是联系。我们的数据不仅将阐明滋养层细胞适应损伤的分子基础，而且还可能为未来的转化研究奠定基础，为妊娠合并胎盘功能障碍的女性提供新的诊断和治疗方法。 公共卫生相关性：胎盘是胚胎发育过程中氧气和营养物质的“唯一来源”，对胎儿发育至关重要。我们的研究旨在阐明胎盘短RNA分子（microRNA）在胎盘适应外部损伤中的作用。我们的实验将拓宽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.