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

• 批准号: 8531361
• 负责人: SOREN IMPEY
• 金额: $ 36.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531361
• 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; public health relevance; recombinase; research study; response; screening; small molecule; synaptogenesis; tool; transcriptome sequencing

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. PUBLIC HEALTH RELEVANCE: microRNAs are small molecules that act as potent silencers of protein expression. With respect to brain health, dysregulation of microRNAs expression has been suggested to contribute to a number of neurological disorders, including Down syndrome, Rett syndrome and schizophrenia. In this proposal, our goal is to provide the first comprehensive examination of how neuronal activity regulates microRNA expression in the adult mammalian central nervous system and, in turn, how microRNA regulates key aspects of neuronal plasticity and pathology. These data should provide a framework to begin to develop therapeutic approaches designed to regulate microRNA expression.

描述（由申请人提供）：MicroRNA是最近表征的一类抑制mRNA翻译的小的非编码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内，来自无切丁酶小鼠的结果支持microRNA在神经元形态发生和神经元存活中的作用。然而，对于神经元活动如何调节成熟神经系统中microRNA的表达模式以及microRNA是否调节神经元可塑性和细胞活力知之甚少。基于一些研究人员最近的工作，以及本文报道的初步数据，我们提出microRNA在成熟神经系统的活性依赖性结构可塑性中起着关键作用。为了验证这一假设，我们组装了一组新的转基因小鼠模型，以及一系列遗传和功能筛选试验。在目的1中，我们提出利用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。我们还将研究活动依赖性神经元可塑性的基础转录网络的贡献，并进行一系列实验，以确定功能相关的microRNA目标。在目标2中，我们提出确定microRNA对成年神经元结构可塑性和神经保护的贡献。为此，我们将采用可诱导形式的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，我们提出确定microRNA-132位点在体内活动诱导的结构重塑中的作用。将使用敲除和tet诱导的microRNA小鼠品系的组合来测试这个问题。这里产生的数据应该提供了丰富的新见解，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。 公共卫生相关性：microRNA是一种小分子，可作为蛋白质表达的有效沉默剂。关于大脑健康，已经表明微RNA表达的失调有助于许多神经系统疾病，包括唐氏综合征、雷特综合征和精神分裂症。在这项提案中，我们的目标是提供第一个全面的检查神经元活动如何调节microRNA在成年哺乳动物中枢神经系统的表达，反过来，microRNA如何调节神经元可塑性和病理学的关键方面。这些数据应该为开始开发旨在调节microRNA表达的治疗方法提供一个框架。