Defining the cell type-specific role of miR-9-2 in telencephalon development

项目摘要 发育过程中基因网络的失调可导致器官畸形、功能障碍和疾病， 特别是神经系统疾病如精神分裂症、亨廷顿氏病和阿尔茨海默氏病。因此， 全面了解在发育过程中活跃的基因调控网络， 中枢神经系统需要更好地了解疾病的病因和治疗。的长期目标 该提案旨在确定microRNA miR-9-2在脑发育、功能和疾病利用中的作用， 体内敲除小鼠模型。我的初步数据显示，在发育过程中miR-9-2的缺失导致了 严重畸形的前脑在小鼠中以基因剂量依赖的方式。基于这一点和以前的研究， 我假设miR-9-2是指导神经祖细胞增殖的基因网络的关键调节因子， 分化和生存。在这里，使用转录组学，基因组学和组织学方法的组合，我 将揭示大脑中miR-9-2调控的基因、基因组调控元件和细胞过程， 我们正在研究如何确定这种重要的microRNA的具体作用。另外，我会发现上游 通过研究高度保守的顺式调控元件的作用来研究miR-9-2表达的调控因子，或 在发育过程中调节miR-9-2表达的增强子。这项研究意义重大，因为 它将提供对基因网络、细胞群和大脑结构的全面了解， 在miR-9-2调控下，深入了解miR-9-2表达的调控，并告知 miR-9-2失调的后果导致神经系统疾病。

PROJECT SUMMARY Dysregulation of gene networks during development can lead to organ malformation, dysfunction and disease, especially neurological diseases such as schizophrenia, Huntington’s and Alzheimer’s disease. Thus, a more comprehensive understanding of the gene regulatory networks that are active during development of the central nervous system are needed to better understand disease etiology and treatment. The long-term goal of this proposal is to define the role of the microRNA miR-9-2 in brain development, function and disease utilizing in vivo knock-out mouse models. My preliminary data show that loss of miR-9-2 during development results in severely malformed forebrains in mice in a gene dose-dependent manner. Based on this and previous studies, I hypothesize that miR-9-2 is a critical regulator of gene networks that instruct neural progenitor proliferation, differentiation and survival. Here, using a combination of transcriptomic, genomic and histological methods, I will uncover the genes, genomic regulatory elements and cellular processes regulated by miR-9-2 during brain development to define the specific role of this important microRNA. Additionally, I will uncover upstream regulators of miR-9-2 expression by investigating the role of a deeply conserved cis-regulatory element, or enhancer in modulating miR-9-2 expression during development. The proposed research is significant because it will provide a comprehensive understanding of the gene networks, cell populations, and brain structures under miR-9-2 regulation, give insight into the regulation of miR-9-2 expression and inform on the consequences of miR-9-2 dysregulation that lead to neurological disease.