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.
The disparity between our current understanding of human pathologies and the underlying causes represents a significant gap in our knowledge. Long noncoding RNAs (lncRNAs) represent a new and understudied area in genome biology and here, I propose to investigate the in vivo functions of a lncRNA in neuronal development and disease. This proposed research relevant to NIH?s mission to understand the complex etiologies of human disease, thereby laying the foundation for advances in disease treatment and prevention.
