The Long Noncoding RNA Firre in Neural Development and Disease

项目摘要 最近的几项研究已经确定，基因组中的许多非编码区与一个基因相关。 各种人类疾病。有趣的是，这些遗传风险区域中有许多包含长的非编码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。我们知识上的这一差距限制了推进诊断的能力， 治疗人类疾病以及开发新的治疗方法。我的长期目标是了解 通过采用新的遗传方法研究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，我已经磨练出一种lncRNA，菲尔， 在核组织中的作用，并与人类发育大脑的知之甚少有关。 病理学，室周结节性异位（PNH），影响皮质神经发生。的目的 我们的建议是确定在Firre过度表达的情况下，皮质神经发生是否受损 并决定基因表达的方式。为了达到这个目的，我将通过使用一种 我最近制作的一种新型小鼠模型。从男性和女性控制组和Firre- 将在神经发育的关键阶段评估过表达小鼠的皮质厚度以及 皮层神经元的数量和身份我的初步数据表明，过表达Firre的小鼠 有较小的皮层区域。为了确定神经细胞中Firre过表达的分子后果， 组织，我将在男性和女性的不同神经发生时间点对神经组织进行RNA-seq 冷杉过度表达小鼠。这项研究意义重大，因为它将首次直接 解决了长的非编码RNA，Firre，在神经发生以及在一个很差的背景下的作用。 研究了发育性神经元疾病PNH。因此，这种新型小鼠可以作为一种新的模型， 了解复杂的发育性神经畸形（PNH）的原因和机制。总的来说， 这种方法将导致对lncRNA的生理作用的迫切需要的理解， 基因调制的结果。

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.