MicroRNA biogenesis and specificity in neurotrophin-dependent protein synthesis

描述（由申请人提供）：健康的认知功能取决于对传入刺激的特定靶向基因的正确调节。脑源性神经营养因子（BDNF）是一种神经营养因子，在神经元存活、分化和突触可塑性中发挥着重要作用。BDNF可在转录和翻译两个层面调控基因表达。BDNF的一些功能，包括树突生长和长期突触可塑性，都明确依赖于BDNF调节蛋白质合成的能力。BDNF通过增强翻译起始因子和延伸因子的活性，在全球范围内诱导蛋白质合成机制，适度增加总神经元蛋白质合成。然而，BDNF表现出高度的转录特异性，并强烈上调一小部分靶标的翻译，同时使一些靶标不受影响，而下调其他靶标的翻译。这种惊人的转录选择性对于BDNF控制神经元蛋白组成及其作为营养因子的作用至关重要。我们最近描述了BDNF通过正向和负向调节成熟mirna的生物发生来控制蛋白质合成特异性的途径，以确定特定基因转录物是被抑制还是被增强翻译。本提案的重点是研究BDNF控制miRNA生物发生的分子机制，这种调节的空间和时间方面，以及这些新途径成分在认知功能中的作用。我们的研究结果将揭示先前未知的控制基因表达特异性的机制，并为治疗与特定过程相关的脑部疾病提供潜在的新治疗靶点，如自闭症、脆性X综合征、抑郁症和神经退行性疾病，这些疾病已知与BDNF或翻译失调有关，或两者兼有。

DESCRIPTION (provided by applicant): Healthy cognitive function depends upon the correct regulation of specific targeted genes in response to incoming stimuli. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with well-established roles in neuronal survival, differentiation, and synaptic plasticity. BDNF can regulate gene expression at the levels of both transcription and translation. Several functions of BDNF, including dendrite outgrowth and long-term synaptic plasticity, are known to explicitly depend upon the ability of BDNF to regulate protein synthesis. BDNF modestly increases total neuronal protein synthesis by enhancing the activity of translation initiation and elongation factors to globally induce the protein synthesis machinery. However, BDNF demonstrates an extraordinary degree of transcript specificity and strongly upregulates the translation of a small percentage of targets, while leaving some targets unaffected and downregulating the translation of others. This striking transcript selectivity is critical to the control of neuronal protein composition by BDNF and its role as a trophic factor. We recently delineated a pathway by which BDNF controls specificity in protein synthesis 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 the molecular mechanisms by which BDNF controls miRNA biogenesis, the spatial and temporal aspects of this regulation, and the role of these novel pathway components in cognitive function. Results from our investigations wil reveal previously unknown mechanisms controlling the specificity of gene expression and offer potential new therapeutic targets for the treatment of brain disorders with particular relevance to processes, such as Autism, Fragile X syndrome, depression, and neurodegenerative disease, with known links to BDNF, dysregulated translation, or both.