The Long Noncoding RNA Firre in Neural Development and Disease

长非编码RNA在神经发育和疾病中的作用

• 批准号: 9395577
• 负责人: Jordan Lewandowski
• 金额: $ 5.71万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395577
• 关键词: Address; Apoptosis; Area; Biological; Biology; Brain; Brain Pathology; Chromosomes; Code; Complex; Data; Development; Developmental Brain Malformation; Diagnosis; Disease; Elements; Etiology; Female; Foundations; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genetic Risk; Genetic Transcription; Genome; Goals; Human; Human Pathology; Immunohistochemistry; Impairment; Individual; Knowledge; Link; Mission; Modality; Modeling; Molecular; Mus; Neurons; Nuclear; Partner in relationship; Pathway interactions; Pattern; Phenotype; Physiological; Prevention; RNA; Research; Role; System; Testing; Tetracyclines; Thick; Time; Tissues; Transcription Coactivator; Translating; United States National Institutes of Health; Untranslated RNA; Work; X Chromosome; brain malformation; genetic approach; genetic signature; genome-wide; human disease; in vivo; in vivo Model; insight; male; malformation; mouse model; neurodevelopment; neurogenesis; neuron development; novel; novel therapeutics; overexpression; rapid growth; relating to nervous system; sex; transcriptome sequencing

PROJECT SUMMARY Several recent studies have identified that many noncoding regions in the genome are associated with a variety of human diseases. Interestingly, many of these genetic risk regions contain long noncoding RNAs (lncRNAs). However, our understanding of the roles that lncRNAs have in normal biology and in human pathologies is lagging far behind. This gap in our knowledge limits the ability to advance the diagnosis and treatment of human disease as well as develop novel therapeutics. My long-term goal is to understand the in vivo functions of lncRNAs in both development and disease by employing novel genetic approaches in mouse models and ex vivo culture systems. Toward this end, I have honed in on a lncRNA, Firre, that has roles in nuclear organization and has been implicated in a poorly understood human developmental brain pathology, periventricular nodular heterotopia (PNH), that effects cortical neurogenesis. The objective of this proposal is to determine whether cortical neurogenesis is impaired in a Firre overexpression context and determine the modalities of gene expression. Toward this end, I will overexpress Firre RNA by using a novel mouse model that I have recently generated. Brains from male and female control and Firre- overexpression mice will be assessed at key stages during neural development for cortical thickness as well as for the number and identity of cortical neurons. My preliminary data indicates that Firre-overexpressing mice have smaller cortical regions. Toward determining the molecular consequences of Firre-overexpression in neural tissue, I will perform performing RNA-seq on neural tissues at different neurogenic time points in male and female Firre overexpressing mice. This proposed research is significant because it will, for the first time, directly address the role of the long noncoding RNA, Firre, in neurogenesis as well as in the context of a poorly studied developmental neuronal disease, PNH. Therefore, this novel mouse could serve as a new model to understand the causes and mechanisms for the complex developmental neural malformation, PNH. Collectively, this approach will lead to a much-needed understanding of the physiological roles of lncRNAs resulting from the consequences of their genetic modulation.

项目概要 最近的几项研究发现，基因组中的许多非编码区域与 各种人类疾病。有趣的是，许多这些遗传风险区域都含有长非编码 RNA （lncRNA）。然而，我们对 lncRNA 在正常生物学和人类中的作用的理解 病理学远远落后。我们知识上的差距限制了推进诊断和治疗的能力 治疗人类疾病并开发新疗法。我的长期目标是了解 通过采用新的遗传方法来研究lncRNA在发育和疾病中的体内功能 小鼠模型和离体培养系统。为此，我研究了一种 lncRNA Firre，它具有 在核组织中的作用，并与我们知之甚少的人类发育大脑有关 病理学，脑室周围结节性异位（PNH），影响皮质神经发生。此举的目的 提议是确定 Firre 过度表达背景下皮质神经发生是否受损 并确定基因表达的方式。为此，我将使用 我最近生成的新颖的鼠标模型。来自男性和女性控制和 Firre 的大脑 将在神经发育的关键阶段评估过度表达小鼠的皮质厚度以及 皮质神经元的数量和身份。我的初步数据表明 Firre 过度表达的小鼠 有较小的皮质区域。确定 Firre 过度表达在神经中的分子后果 组织，我将对男性和女性不同神经源性时间点的神经组织进行 RNA 测序 Firre 过度表达小鼠。这项拟议的研究意义重大，因为它将首次直接 解决长非编码 RNA Firre 在神经发生以及在神经发育不良的情况下的作用 研究了发育神经元疾病（PNH）。因此，这种新型小鼠可以作为一种新模型 了解复杂的发育性神经畸形 (PNH) 的原因和机制。总的来说， 这种方法将导致人们对 lncRNA 的生理作用产生急需的理解 它们的基因调节的后果。