Activity-dependent microRNA expression and function in the mature nervous system

成熟神经系统中活性依赖性的 microRNA 表达和功能

基本信息

批准号：
8730236
负责人：
SOREN IMPEY
金额：
$ 37.76万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730236
关键词：
Address Adult Affect Binding Sites Bioinformatics Biological Assay Brain CREB1 gene Cell Death Cell Survival Cells ChIP-seq Data Data Reporting Data Set Dendritic Spines Development Developmental Process Disease Down Syndrome Excision Functional RNA Genes Genetic Genetic Translation Goals Growth Health Hippocampus (Brain)Immunoprecipitation In Situ Hybridization Knock-out Knockout Mice Learning Maps Mediating Messenger RNA Methods MicroRNAs Morphogenesis Mouse Strains Mutant Strains Mice Nervous system structure Neuraxis Neuronal Plasticity Neurons Pathology Pathway interactions Pattern Physiological Play Process Proteins RNA Regulation Reporter Reporting Research Personnel Rett Syndrome Role Schizophrenia Seizures Series Small RNA Stimulus System Tamoxifen Testing Tetanus Helper Peptide Therapeutic Time Transgenic Organisms Validation Vertebral column Work axonal sprouting base comparative deep sequencing dentate gyrus design granule cell human DICER1 protein in vivo innovation insight loss of function mouse model nervous system disorder neuronal survival neuroprotection novel protein expression recombinase research study response screening small molecule synaptogenesis tool transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): MicroRNA is a recently characterized class of small, non-coding, RNA that repress mRNA translation. Work over the past several years has revealed important roles for microRNA in a vast array of developmental and disease-related processes. Within the developing mammalian central nervous system, results from dicer null mice support a role for microRNAs in neuronal morphogenesis and neuronal survival. However, relatively little is known about how neuronal activity regulates microRNA expression patterns in the mature nervous system and, importantly, whether microRNA regulate neuronal plasticity and cell viability. Based on recent work by a number of investigators, and on the preliminary data reported here, we propose that microRNA plays a key role in activity-dependent structural plasticity in the mature nervous system. To test this hypothesis we have assembled a novel set of genetically modified mouse models, and an array of genetic and functional screening assays. In Aim 1, we propose to utilize the Solexa deep sequence method to examine activity-dependent expression of non-coding RNA in the hippocampus. We will also examine the contribution of transcriptional networks that underlie activity-dependent neuronal plasticity and perform a series of experiments to identify functionally relevant microRNA targets. In Aim 2 we propose to determine the contribution of microRNA to adult neuronal structural plasticity and neuroprotection. To this end, we will employ an inducible form of Cre-recombinase to disrupt Dicer expression. The effects on both physiological and pathophysiological levels of neuronal activity will be examined. In Aim 3, we propose to determine the role of the microRNA-132 locus in activity-induced structural remodeling in vivo. A combination of knockout and tet-inducible microRNA mouse strains will be used to test this question. The data generated here should provide a wealth of new insights regarding how neuronal activity sculpts microRNA expression patterns, and, in turn, how these changes affect key aspects of neuronal plasticity and pathology.

描述（由申请人提供）：MicroRNA 是最近鉴定的一类抑制 mRNA 翻译的小型非编码 RNA。过去几年的工作揭示了 microRNA 在大量发育和疾病相关过程中的重要作用。在发育中的哺乳动物中枢神经系统中，dicer null 小鼠的结果支持 microRNA 在神经元形态发生和神经元存活中的作用。然而，关于神经元活动如何调节成熟神经系统中的 microRNA 表达模式，以及重要的是，microRNA 是否调节神经元可塑性和细胞活力，人们知之甚少。根据许多研究人员最近的工作以及此处报告的初步数据，我们提出 microRNA 在成熟神经系统中的活动依赖性结构可塑性中发挥着关键作用。为了检验这一假设，我们组装了一套新颖的转基因小鼠模型，以及一系列遗传和功能筛选测定。在目标 1 中，我们建议利用 Solexa 深度序列方法来检查海马中非编码 RNA 的活性依赖性表达。我们还将研究转录网络对活动依赖性神经元可塑性的贡献，并进行一系列实验来识别功能相关的 microRNA 靶点。在目标 2 中，我们建议确定 microRNA 对成人神经元结构可塑性和神经保护的贡献。为此，我们将采用诱导型 Cre 重组酶来破坏 Dicer 表达。将检查对神经元活动的生理和病理生理水平的影响。在目标 3 中，我们建议确定 microRNA-132 位点在活动诱导的体内结构重塑中的作用。敲除小鼠和 tet 诱导型 microRNA 小鼠品系的组合将用于测试这个问题。这里生成的数据应该提供大量关于神经元活动如何塑造 microRNA 表达模式，以及这些变化如何影响神经元可塑性和病理学的关键方面的新见解。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Phosphorylation of CREB at Serine 133 Is a Key Event for Circadian Clock Timing and Entrainment in the Suprachiasmatic Nucleus.

DOI：
10.1177/0748730418791713
发表时间：
2018-10
期刊：
Journal of biological rhythms
影响因子：
3.5
作者：
Wheaton KL;Hansen KF;Aten S;Sullivan KA;Yoon H;Hoyt KR;Obrietan K
通讯作者：
Obrietan K

miR-132 couples the circadian clock to daily rhythms of neuronal plasticity and cognition.

DOI：
10.1101/lm.047191.117
发表时间：
2018-05
期刊：
Learning & memory (Cold Spring Harbor, N.Y.)
影响因子：
0
作者：
Aten S;Hansen KF;Price KH;Wheaton K;Kalidindi A;Garcia A;Alzate-Correa D;Hoyt KR;Obrietan K
通讯作者：
Obrietan K

Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits.

DOI：
10.1016/j.bbr.2016.04.027
发表时间：
2016-07-15
期刊：
Behavioural brain research
影响因子：
2.7
作者：
Price KH;Dziema H;Aten S;Loeser J;Norona FE;Hoyt K;Obrietan K
通讯作者：
Obrietan K

Profiling status epilepticus-induced changes in hippocampal RNA expression using high-throughput RNA sequencing.

DOI：
10.1038/srep06930
发表时间：
2014-11-06
期刊：
Scientific reports
影响因子：
4.6
作者：
Hansen KF;Sakamoto K;Pelz C;Impey S;Obrietan K
通讯作者：
Obrietan K

Circadian expression and functional characterization of PEA-15 within the mouse suprachiasmatic nucleus.

小鼠视交叉上核内 PEA-15 的昼夜节律表达和功能特征。

DOI：
10.1111/ejn.13850
发表时间：
2018
期刊：
The European journal of neuroscience
影响因子：
0
作者：
Wheaton,Kelin;Aten,Sydney;Queiroz,LucasSales;Sullivan,Kyle;Oberdick,John;Hoyt,KariR;Obrietan,Karl
通讯作者：
Obrietan,Karl