Mechanisms and Function of NF-kappaB Activation at Dendritic Spines

树突棘 NF-kappaB 激活的机制和功能

• 批准号: 8705190
• 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: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705190
• 关键词: Alzheimer' 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; research study; response; synaptic function; 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-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）：响应传入的神经元刺激而正确调节特定靶基因对于健康的认知功能至关重要。 NF-kappaB 是一种转录因子，在突触可塑性、学习和记忆中具有成熟且进化保守的作用。特别是，已知神经元 NF-κB 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突触功能的基因表达。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，高通量方法强调了细胞 mRNA 和相应蛋白质组谱中经常不一致的关系，这表明在理解刺激依赖性基因表达程序时还必须考虑额外水平的转录后控制。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 的生物发生来建立基因表达的转录后特异性，以确定特定基因转录本是否受到抑制或经历增强的翻译。该提案的重点是研究 NF-kappaB 对活动依赖性神经元基因表达进行转录和转录后控制的新分子机制，包括这种调节的空间和时间方面。我们提出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靶点特异性和维持基因表达变化的机制，并为治疗自闭症、抑郁症、21三体症、脑癌和神经退行性疾病等脑部疾病提供潜在的新治疗靶点，这些疾病与基因表达失调有关。