权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms and Function of NF-kappaB Activation at Dendritic Spines

树突棘 NF-kappaB 激活的机制和功能

基本信息

批准号：
8722033
负责人：
MOLLIE Katherine MEFFERT
金额：
$ 40.5万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8722033
关键词：
Alzheimer&apos s Disease Animals Autistic Disorder Behavioral Binding Binding Sites Biogenesis Brain Brain Diseases Brain region Brain-Derived Neurotrophic Factor Cells Complement Cytoplasm Data Dementia Dendritic Spines Dicer Enzyme Down Syndrome Ensure Epigenetic Process Excitatory Synapse Family Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Glutamates Growth Image Immunohistochemistry Information Storage Investigation Lead Learning Life Link Maintenance Malignant neoplasm of brain Mediating Memory Mental Depression Messenger RNA MicroRNAs Modeling Molecular Molecular Profiling Mus NF-kappa B Neurodegenerative Disorders Neurons Neurotransmitters Nuclear Translocation Obsessive-Compulsive Disorder Oncogenic Output Pathway interactions Physiological Post-Transcriptional Regulation Process Protein Biosynthesis Proteins Proteome RNA-Binding Proteins Regulation Repression Research Role Schizophrenia Shapes Specificity Stimulus Synapses Synaptic plasticity TNFRSF5 gene Transcript Transcriptional Regulation Translations Up-Regulation Work age related cognitive function dimer follow-up in vitro Assay inhibitor/antagonist mammalian genome member nervous system disorder neurotransmission neurotrophic factor new therapeutic target novel p65 paralogous gene prevent programs protein B research study response synaptic function transcription factor

项目摘要

DESCRIPTION (provided by applicant): The correct regulation of specific target genes in response to incoming neuronal stimuli is essential to healthy cognitive function. NF-kappaB is a transcription factor with well- established and evolutionarily-conserved roles in synaptic plasticity, learning, and memory. In particular, neuronal NF-kappaB is known to be activated by both excitatory neurotransmission and neurotrophic factors, and to regulate the expression of genes that promote the growth and enhance the function of excitatory synapses. However, mechanisms responsible for determining the duration of NF-kappaB-dependent gene expression and for insuring the appropriate stimulus-specific selection of target genes remain unclear. In recent years, high-throughput approaches have highlighted frequently discordant relationships in the profiles of cellular mRNAs and the corresponding proteomes, indicating that additional levels of post-transcriptional control must also be considered in understanding stimulus-dependent programs of gene expression. We recently delineated a pathway by which post-transcriptional specificity in gene expression can be established through both positively and negatively regulating the biogenesis of mature miRNAs to determine whether specific gene transcripts are repressed or undergo enhanced translation. The focus of this proposal is to examine novel molecular mechanisms by which NF-kappaB may exert transcriptional and post-transcriptional control over activity-dependent neuronal gene expression, including both spatial and temporal aspects of this regulation. Our proposed research incorporates approaches ranging from the cellular and molecular level, to behavioral studies. Results from our investigations will reveal previously unknown mechanisms controlling the target specificity and maintenance of changes in gene expression and offer potential new therapeutic targets for the treatment of brain disorders, such as Autism, depression, Trisomy 21, brain cancer and neurodegenerative disease, with known links to dysregulated gene expression.

描述（由申请人提供）：响应传入神经元刺激的特定靶基因的正确调节对健康的认知功能至关重要。NF-κ B是一种转录因子，在突触可塑性、学习和记忆中具有公认的和进化上保守的作用。特别地，已知神经元NF-κ B被兴奋性神经传递和神经营养因子激活，并调节促进兴奋性突触的生长和增强其功能的基因的表达。然而，负责确定NF-κ B依赖性基因表达的持续时间和确保靶基因的适当刺激特异性选择的机制仍不清楚。近年来，高通量的方法已经突出了经常不一致的关系，在细胞的mRNA和相应的蛋白质组的配置文件，表明额外的水平的转录后控制也必须考虑在理解刺激依赖的程序的基因表达。我们最近描绘了一条途径，通过该途径可以通过正向和负向调节成熟miRNA的生物发生来确定特定基因转录物是否被抑制或经历增强的翻译，从而建立基因表达的转录后特异性。这项建议的重点是研究新的分子机制，NF-κ B可能发挥转录和转录后控制活性依赖的神经元基因表达，包括空间和时间方面的这种调节。我们提出的研究包括从细胞和分子水平到行为研究的方法。我们的研究结果将揭示以前未知的机制，控制靶点特异性和维持基因表达的变化，并提供潜在的新的治疗靶点，用于治疗大脑疾病，如自闭症，抑郁症，21三体，脑癌和神经退行性疾病，已知与基因表达失调有关。