miR-137 Regulation of Intrinsic Excitability

miR-137 内在兴奋性的调节

基本信息

批准号：
10719579
负责人：
SUSAN L TSUNODA
金额：
$ 40.9万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10719579
关键词：
3&apos Untranslated Regions AMPA Receptors Affect Algorithms Animals Behavior Biochemistry Biological Assay Biological Models Biology Bipolar Disorder Brain Brain Diseases CRISPR/Cas technology Cells Cognitive Data Defect Dendrites Development Disease Drosophila genus Electrophysiology (science)Embryo Event Functional disorder Gene Expression Gene Targeting Generations Genes Genetic Genetic Transcription Genome Genomics Goals Health Hippocampus Human Individual Intellectual functioning disability Ion Channel Ions Knock-out Lead Learning Link Long-Term Depression Long-Term Potentiation Mediating Memory Messenger RNA MicroRNAs Modeling Molecular Genetics Morphogenesis Mus Nervous System Neurologic Neurons Nucleotides Phenotype Physiological Play Point Mutation Potassium Channel Regulation Reporting Role Schizophrenia Shapes Signal Transduction Single Nucleotide Polymorphism Site Sodium Channel Synapses Synaptic Transmission Synaptic plasticity System T-Type Calcium Channels Testing Transgenic Organisms Translations Untranslated RNA Vertebral column anxiety-like behavior autism spectrum disorder electrical property fly genetic manipulation in vivo insight mutant nervous system development neurogenesis neuronal excitability neuropsychiatry neurotransmission neurotransmitter release overexpression postsynaptic protein expression response social synaptic function synaptogenesis tool ubiquitin ligase

项目摘要

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.

项目概要 miRNA 是小型、内源性、非编码 RNA，越来越多的证据表明它们发挥着重要作用 miR-137 是一种高度保守的大脑富集 miRNA，已被证实在调节基因表达中发挥作用。多种脑部疾病，包括精神分裂症、自闭症谱系障碍 (ASD)、双相情感障碍和我们的长期目标是确定影响内在的 miR-137 的所有基因靶标。神经兴奋性，并了解这些调节事件如何、何时、何地影响信号传导在拟议的研究中，我们将首先研究内在和突触的可塑性。神经元的活性随着 miR-137 表达水平的改变而改变，然后确定 miR-137 有助于改变体内兴奋性，我们将使用果蝇作为实验系统。结合强大的分子遗传学工具，包括 CRISPR-Cas9 技术来制作定点基因组变化，通过生物化学和电生理学来检查：1）神经元的内在电活动如何受 miR-137 调节，2) 离子通道基因，包括 Kv4/Shal、Kv3/Shaw、KCNH/eag、Cav3/Ca-α1T、和 Nav1/对离子通道基因，以及其他活性相关靶标，受 miR-137 调节以影响体内神经兴奋性。