Role of LincRNA in Developmental Regulation of Angiogenesis

描述（由申请人提供）：从胎儿到成人的发育成熟与动脉血管生成潜能的变化有关。重要的是，血管生成反应是由血管生成基因的协调转录和翻译调节。在目前的提案中，我们将研究一类新的调控RNA分子，即长链非编码RNA （lncRNAs）在胎儿和成人脑动脉血管生成的发育调控中的作用。在小鼠的18万多个转录本中，有2万个是蛋白质编码基因，其余16万个中大部分是lncRNA。这些lncRNA序列大多保守性差，被认为是转录“噪音”。然而，lncRNA的一个子集有自己的启动子，并且在哺乳动物中保守得很好。这一组被称为长基因间非编码RNA （lincRNA）。这个群体被认为在细胞分化、运动以及通过改变基因表达模式对细胞状态进行重编程中发挥着强有力的分子开关作用。在血管生成中具有细胞和分子功能的lincrna的鉴定将为发现新的调控途径提供一个令人兴奋的机会，这可能会导致更好地理解这一重要过程。因此，我们建议鉴定和描述lincrna在调节血管生成发育中的作用。我们的具体目标是识别和分析胎儿和成年绵羊脑动脉中通过功能筛选的丧失或获得参与内皮活化的候选lincrna。我们的实验方法的基本原理是，它将允许对lincrna在血管生成和成熟变化中的尚未表征的作用进行仔细的、特定阶段的解剖。它也有可能为血管瘤、癌症的发病机制提供见解，并有助于实现再生医学和组织工程中调节血管生成的潜力。

DESCRIPTION (provided by applicant): Developmental maturation from fetus to adult is associated with changes in the angiogenic potential of arteries. Importantly, angiogenic response is regulated by a coordinated transcriptional and translational regulation of angiogenesis genes. In the present proposal, we will examine the role of a new class of regulatory RNA molecules known as long non-coding RNAs (lncRNAs) in developmental regulation of angiogenesis in fetus and adult cerebral arteries. Out of more than 180,000 transcripts in mouse, 20,000 are the protein coding genes and majorities of the remaining 160,000 are lncRNA. Most of these lncRNA sequences are poorly conserved and have been regarded as transcriptional "noise". However, a subset of lncRNA has its own promoter, and is well conserved in mammals. This group is known as long intergenic non-coding RNA (lincRNA). This group is known for acting as potent molecular switch in cellular differentiation, movement, as well as in reprogramming of cell states by altering gene expression patterns. Identification of lincRNAs with cellular and molecular functions in angiogenesis will provide an exciting opportunity to discover new regulatory pathways that may lead to a better understanding of this vital process. Thus, we propose to identify and characterize the role of lincRNAs in regulating angiogenesis with development. Our specific aims will identify and analyze candidate lincRNAs involved in endothelial activation by a loss or gain of function screen in fetal and adult ovine cerebral arteries. The rationale for our experimental approach is that it will allow a careful, stage-specific dissection of the yet uncharacterized roles of lincRNAs in angiogenesis and changes with maturation. It also has the potential to provide insights into the pathogenesis of hemangioma, cancer, as well as contribute in efforts to realize the potential of regulated angiogenesis for regenerative medicine and tissue engineering.