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

• 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
• 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' 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

 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）：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-κB是一种转录因子，在突触可塑性、学习和记忆中具有公认和进化保守的作用。特别地，已知神经元NF-κB被兴奋性神经传递因子和神经营养因子激活，并且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适当的刺激特异性选择靶基因的机制仍不清楚。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。该提案的重点是研究NF-κB可能对活动依赖性神经元基因表达施加转录和转录后控制的新型分子机制，包括这种调节的定性和时间方面。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目标的特异性和基因表达的变化的维护。这种基础知识的获得将增强我们对正常和异常脑功能的理解，并有可能加速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。