Mechanisms and Function of NF-kappaB Activation at Dendritic Spines

描述(由申请人提供)：对传入的神经元刺激作出反应的特定目标基因的正确调控对健康的认知功能至关重要。核因子-kappaB是一种转录因子，在突触可塑性、学习和记忆中具有成熟的和进化上保守的作用。尤其是神经元核因子-kappaB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生长和增强功能的基因的表达。然而，负责确定依赖于核因子-kappaB的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，高通量方法经常强调细胞mRNAs和相应蛋白质组之间的不一致关系，这表明在理解刺激依赖的基因表达程序时，还必须考虑额外的转录后调控水平。我们最近描述了一条途径，通过对成熟miRNAs的生物发生进行正向和负向调控来确定特定基因转录产物是被抑制还是经历增强翻译，从而建立基因表达的转录后特异性。这一建议的重点是研究新的分子机制，通过这些机制，NF-kappaB可以对活性依赖的神经元基因表达进行转录和转录后控制，包括这种调控的空间和时间两个方面。我们建议的研究结合了从细胞和分子水平到行为研究的各种方法。我们的研究结果将揭示以前未知的控制靶标特异性和维持基因表达变化的机制，并为治疗大脑疾病提供潜在的新治疗靶点，如自闭症、抑郁症、21三体、脑癌和神经退行性疾病，已知与基因表达异常有关。

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.