Mechanisms and Functions of NF-kB-Regulated Neuronal Gene Expression

NF-kB调节神经元基因表达的机制和功能

基本信息

批准号：
9268079
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：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9268079
关键词：
Alpha Cell Alzheimer&apos s Disease Animals Binding Binding Sites Biogenesis Brain Brain Diseases Cognitive Complement Complex Data Dementia Development Dimerization Ensure Enzymes Epigenetic Process Excitatory Synapse Family Frequencies Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Growth Hippocampus (Brain)Income Individual Information Storage Investigation Knowledge Learning Link Maintenance Malignant neoplasm of brain Mediating Memory Messenger RNA MicroRNAs Modeling Molecular Molecular Profiling Mus NF-kappa B Neurodegenerative Disorders Neurons Nuclear Translocation Oncogenic Pathway interactions Physiological Post-Transcriptional Regulation Process Protein Biosynthesis Proteins Proteome RNA-Binding Proteins Regulation Repression Research Role Shapes Signal Transduction Specificity Stimulus Synapses Synaptic plasticity TNFRSF5 gene Transcript Transcriptional Regulation Translations Up-Regulation Vitronectin Work age related behavioral study brain abnormalities cognitive function dimer follow-up in vitro Assay inhibitor/antagonist mammalian genome member nervous system disorder neurotransmission neurotrophic factor neurotropin new therapeutic target novel p65 paralogous gene pre-clinical therapy prevent programs public health relevance repaired response synaptic function therapy development 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-κB is a transcription factor with well- established and evolutionarily-conserved roles in synaptic plasticity, learning, and memory. In particular, neuronal NF-κB 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-κB-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-κB may exert transcriptional and post-transcriptional control over activity-dependent neuronal gene expression, including both qualitative 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. This gain in fundamental knowledge will enhance our understanding of normal and abnormal brain function and has the potential to accelerate preclinical therapy development for disorders of brain plasticity and repair, brain cancer, and neurodegenerative diseases, with known links to dysregulated gene expression.

描述（由申请人提供）：对传入神经元刺激做出反应的特定靶基因的正确调节对于健康的认知功能至关重要。特别是，已知神经元 NF-κB 可被兴奋性神经传递和神经营养因子激活，并调节促进生长和增强兴奋性功能的基因表达。然而，负责确定 NF-κB 依赖性基因表达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，高通量方法强调了突触谱中经常不一致的关系。细胞 mRNA 和相应的蛋白质组，表明在理解基因表达的刺激依赖性程序时还必须考虑额外水平的转录后控制，我们最近描述了可以建立基因表达转录后特异性的途径。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受到抑制或增强翻译，该提案的重点是检查 NF-κB 可能对活性进行转录和转录后控制的新分子机制。依赖的神经元基因表达，包括这种调节的定性和时间方面，我们的研究结合了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控制目标特异性和变化维持的机制。在基因表达方面。基础知识的获得将增强我们对正常和异常大脑功能的理解，并有可能加速大脑可塑性和修复障碍、脑癌和神经退行性疾病的临床前治疗开发，这些疾病与基因表达失调有关。