Role of LincRNA in Developmental Regulation of Angiogenesis

描述（由申请方提供）：从胎儿到成人的发育成熟与动脉血管生成潜力的变化相关。重要的是，血管生成反应受血管生成基因的协调转录和翻译调控。在本研究中，我们将研究一类新的调控RNA分子，即长链非编码RNA（lncRNA）在胎儿和成人脑动脉血管生成发育调控中的作用。在小鼠的180，000多个转录物中，20，000个是蛋白质编码基因，其余160，000个中的大多数是lncRNA。这些lncRNA序列中的大多数保守性差，被认为是转录“噪音”。然而，lncRNA的一个子集具有其自身的启动子，并且在哺乳动物中是很保守的。这一组被称为长基因间非编码RNA（lincRNA）。已知该基团在细胞分化、运动以及通过改变基因表达模式来重编程细胞状态中充当有效的分子开关。在血管生成中具有细胞和分子功能的lincRNA的鉴定将提供一个令人兴奋的机会，以发现新的调控途径，从而更好地理解这一重要过程。因此，我们提出鉴定和表征lincRNA在调节血管生成与发育中的作用。我们的具体目标是通过在胎儿和成年绵羊脑动脉中功能筛选的丧失或获得来鉴定和分析参与内皮激活的候选lincRNA。我们的实验方法的基本原理是，它将允许对lincRNA在血管生成中的尚未表征的作用和随成熟的变化进行仔细的、阶段特异性的解剖。它也有可能提供深入了解血管瘤，癌症的发病机制，以及有助于努力实现再生医学和组织工程的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.