Role of LincRNA in Developmental Regulation of Angiogenesis

LincRNA 在血管生成发育调控中的作用

• 批准号: 8885866
• 负责人: William J. Pearce
• 金额: $ 19.26万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885866
• 关键词: Adult; Angiogenesis Inhibition; Arteries; Biological Assay; Blood Vessels; Blood capillaries; Carotid Arteries; Cells; Chief Cell; Code; Complex; Corneal Neovascularization; Culture Media; Custom; Data; Development; Disease; Dissection; Endothelial Cells; Epigenetic Process; Fetal Development; Fetus; Fibroblasts; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Growth; Health; Hemangioma; In Vitro; Island; Lead; Life; Malignant Neoplasms; Mammals; Molecular; Movement; Mus; Newborn Infant; Noise; Oligonucleotide Microarrays; Pathogenesis; Pathway interactions; Pattern; Phase; Phenotype; Placental Insufficiency; Play; Pregnancy; Process; Proteins; RNA; Regenerative Medicine; Regulation; Regulatory Pathway; Role; Serum; Sheep; Smooth Muscle Myocytes; Staging; Technology; Therapeutic; Tissue Engineering; Transcript; Transcriptional Regulation; Translational Regulation; Tube; Untranslated RNA; Up-Regulation; Wound Healing; angiogenesis; arteriole; capillary; cell type; cerebral artery; fetal; fetal bovine serum; gain of function; innovation; insight; novel; promoter; regenerative; research study; response; tumor

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.

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相关。重要的是，血管生成反应是通过血管生成基因的协调转录和翻译调节来调节的。在本提案中，我们将研究一类称为长非编码RNA（lncRNA）的新型调节RNA分子在胎儿和成人脑动脉血管生成的发育调节中的作用。在小鼠的 180,000 多个转录本中，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序列大多数保守性较差，被视为转录“噪音”。然而，lncRNA 的一个子集有自己的启动子，并且在哺乳动物中非常保守。该组被称为长基因间非编码RNA (lincRNA)。该基团因在细胞分化、运动以及通过改变基因表达模式来重新编程细胞状态中充当有效的分子开关而闻名。鉴定在血管生成中具有细胞和分子功能的 lincRNA 将为发现新的调控途径提供令人兴奋的机会，从而更好地理解这一重要过程。因此，我们建议鉴定和表征 lincRNA 在调节血管生成和发育中的作用。我们的具体目标是通过胎儿和成年绵羊脑动脉功能丧失或获得的筛查来识别和分析参与内皮激活的候选 lincRNA。我们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尚未表征的作用进行仔细、阶段性的剖析。它还具有深入了解血管瘤、癌症的发病机制的潜力，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。