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力的变化有关。重要的是，血管生成反应是由血管生成基因的转录和翻译协调调节的。在目前的提案中，我们将研究一类新的调控RNA分子，称为长非编码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180,000多个转录本中，有20,000个是蛋白质编码基因，剩下的160,000个转录本中的大部分是lncRNA。这些lncRNA序列大多保守程度较低，被认为是转录上的“噪音”。然而，lncRNA的一个子集有它自己的启动子，并且在哺乳动物中非常保守。这一组被称为长基因间非编码RNA(LincRNA)。众所周知，这个组在细胞分化、运动以及通过改变基因表达模式重新编程细胞状态方面扮演着强有力的分子开关的角色。识别在血管生成中具有细胞和分子功能的lincRNAs将提供一个令人兴奋的机会，发现新的调控途径，可能导致更好地理解这一重要过程。因此，我们建议识别和表征lincRNAs在调节血管生成和发育中的作用。我们的具体目标是识别和分析通过胎儿和成年绵羊脑动脉功能屏蔽的丧失或获得而参与内皮激活的候选lincRNAs。我们实验方法的基本原理是，它将允许仔细地、分阶段地剖析lincRNAs在血管生成和成熟过程中尚未确定的作用。它还有可能为血管瘤和癌症的发病机制提供见解，以及为实现再生医学和组织工程中受调控的血管生成的潜力做出贡献。

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.