miR-137 Regulation of Intrinsic Excitability

项目摘要 miRNAs是一种小的内源性非编码RNA，越来越多的研究表明，miRNAs在肿瘤的发生发展中起着重要的作用。 调节基因表达的作用。miR-137是一种高度保守的脑内富集的miRNA， 多种大脑疾病，包括精神分裂症，自闭症谱系障碍（ASD），双相情感障碍， 智力残疾。我们的长期目标是确定miR-137的所有基因靶点，这些基因靶点影响内在的细胞凋亡。 神经元的兴奋性，并了解如何，何时，以及在这些调节事件有助于信号 和神经系统的可塑性。在拟议的研究中，我们将首先研究如何内在和突触 神经元中的活性响应于miR-137表达水平的改变而改变，然后确定miR-137的靶点。 miR-137在体内改变兴奋性。使用果蝇作为实验系统，我们将 联合收割机强大的分子遗传工具，包括CRISPR-Cas9技术， 变化，生物化学和电生理学检查：1）神经元的内在电活动是如何 受miR-137调节，和2）如果离子通道基因，包括Kv 4/Shal、Kv 3/Shaw、KCNH/eag、Cav 3/Ca-α 1 T， 和Nav 1/帕拉离子通道基因，以及其他活性相关的靶点，受miR-137调控， 体内神经元兴奋性。

Project Summary miRNAs are small, endogenous, non-coding RNAs that are increasingly being shown to play important roles in regulating gene expression. miR-137 is a highly conserved brain-enriched miRNA that has been linked to multiple brain disorders, including schizophrenia, autism spectrum disorder (ASD), bipolar disorder, and intellectual disability (ID). Our long-term goal is to identify all of the gene targets of miR-137 that affect intrinsic neuronal excitability, and understand how, when, and where these regulatory events contribute to signaling and plasticity in the nervous system. In the proposed studies, we will first examine how intrinsic and synaptic activity in neurons is changed in response to altered expression levels of miR-137, then identify the targets of miR-137 that contribute to altered excitability in vivo. Using Drosophila as an experimental system, we will combine powerful molecular-genetic tools, including CRISPR-Cas9 technology to make site-directed genomic changes, with biochemistry and electrophysiology to examine: 1) how intrinsic electrical activity in neurons is regulated by miR-137, and 2) if ion channel genes, including Kv4/Shal, Kv3/Shaw, KCNH/eag, Cav3/Ca-α1T, and Nav1/para ion channel genes, as well as other activity-related targets, are regulated by miR-137 to affect neuronal excitability in vivo.