The Long Noncoding RNA Firre in Neural Development and Disease

项目总结 最近的几项研究发现，基因组中的许多非编码区与一种 各种人类疾病。有趣的是，许多这些遗传风险区域都含有长的非编码RNA (LncRNAs)。然而，我们对lncRNA在正常生物学和人类中所起作用的理解 病理学远远落后于此。我们知识上的这种差距限制了推进诊断和诊断的能力 人类疾病的治疗以及开发新的治疗方法。我的长期目标是了解 利用新的遗传学方法研究lncRNAs在发育和疾病中的活体功能 小鼠模型和体外培养系统。为此，我研究了一种新的核糖核酸，Firre，它已经 在核组织中的作用，并被认为与了解甚少的人类发育大脑有关 病理学，脑室周围结节异位(PNH)，影响皮质神经发生。这样做的目的是 建议是确定在首次过度表达的情况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 我最近制作的新奇的老鼠模型。大脑来自男性和女性的对照和FIRE- 将在神经发育的关键阶段评估过度表达的小鼠的皮质厚度以及 大脑皮层神经元的数量和身份。我的初步数据显示FIRE过度表达的小鼠 有较小的皮质区域。确定FIRE在神经中过度表达的分子后果 组织，我将在不同的神经发生时间点对男性和女性的神经组织进行RNA-seq FIRE过度表达小鼠。这项拟议的研究具有重要意义，因为它将首次直接 解决长的非编码RNA，FIRE，在神经发生以及在不良的 研究发育性神经元疾病，PNH。因此，这种新奇的老鼠可以作为一种新的模型 了解复杂发育性神经畸形的原因和机制。总而言之， 这一方法将导致对lncRNAs生理作用的迫切需要的理解，该生理作用由 它们的基因调控的后果。

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.