BDNF regulation of the cortical neuron transcriptome

 描述(申请人提供)：脑源性神经营养因子(BDNF)是一种分泌型多肽生长因子，是哺乳动物大脑中突触发育和可塑性的主要调节因子。由于有证据表明BDNF信号在许多神经发育、神经退行性和精神障碍中失调，BDNF所利用的调节通路被认为与这些疾病的病理生理学有关。BDNF调控新突触的形成和现有突触的修饰，部分是通过调节特定信使RNAs的转录、调节mRNA翻译启动和特定蛋白质功能的翻译后调节来实现的。尤其是，BDNF对突触的形成和学习记忆的影响，尤其是从信使核糖核酸中翻译新的多肽是必不可少的。然而，受这种监管的一整套特定的mRNAs和涉及的相关监管机制尚未完全确定。这一建议的目的是全面鉴定其丰度和翻译受脑源性神经营养因子(BDNF)强烈调控的mRNAs集合，重点关注抑制神经元，对其翻译调控知之甚少。同时，我们将识别microRNAs，这是一类重要的调控RNA，受到BDNF的强烈调控，以努力揭示BDNF调节mRNA丰度和翻译的机制。这些从原代培养的神经元和遗传操作的小鼠获得的数据集，将通过生物信息学方法进行分析，以确定在突触发育和功能方面至关重要的候选BDNF调控途径，并最终将成为FEL的有用资源。

 DESCRIPTION (provided by applicant): Brain-derived neurotrophic factor (BDNF) is a secreted polypeptide growth factor that is a major regulator of synapse development and plasticity in the mammalian brain. As there is evidence for dysregulation of BDNF signaling in many neurodevelopmental, neurodegenerative, and psychiatric disorders, the regulatory pathways utilized by BDNF are believed relevant to the pathophysiology of these disorders. BDNF controls the formation of new synapses and modification of existing synapses in part through regulation of the transcription of specific messenger RNAs (mRNAs), the regulation of mRNA translation initiation, and the post-translational modulation of specific protein functions. I particular, the translation of new polypeptides from mRNA has been shown to be essential for effects of BDNF on synapse formation and learning and memory. However, the complete set of specific mRNAs subject to such regulation and the relevant regulatory mechanisms involved have not been fully determined. The objective of this proposal is to comprehensively identify the collection of mRNAs whose abundance and translation are acutely regulated by Brain-derived neurotrophic factor (BDNF) with a specific focus on inhibitory neurons, for which little is known regarding translation regulation. In parallel, we will identify microRNAs, an important class of regulatory RNAs, which are acutely regulated by BDNF in an effort to uncover mechanisms by which BDNF modulates mRNA abundance and translation. These datasets, obtained from both primary cultured neurons and genetically manipulated mice, will be analyzed with bioinformatic approaches to identify candidate BDNF- regulated pathways important in synapse development and function both in vitro and in vivo, and will ultimately serve as a useful resource for the fiel.