MicroRNA biogenesis and specificity in neurotrophin-dependent protein synthesis

神经营养蛋白依赖性蛋白质合成中的 MicroRNA 生物发生和特异性

基本信息

批准号：
8877630
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8877630
关键词：
Accounting Adult Alzheimer&apos s Disease Animal Model Autistic Disorder Binding Binding Sites Biogenesis Biological Models Brain Brain Diseases Brain-Derived Neurotrophic Factor Cells Chromatin Cognitive deficits Complement Data Defect Dementia Dendrites Dicer Enzyme Elements Elongation Factor Employee Strikes Ensure Family Fragile X Syndrome Gene Expression Gene Targeting Genes Genetic Polymorphism Genetic Transcription Growth Human Investigation Knowledge Label Laboratories Learning Left Link Mediating Memory impairment Mental Depression Messenger RNA Metabolic MicroRNAs Molecular Mus Neuraxis Neurocognitive Neurodegenerative Disorders Neurons Obsessive-Compulsive Disorder Output Pathway interactions Peptide Initiation Factors Polyribosomes Process Prosencephalon Protein Biosynthesis Proteins Proteome RNA-Binding Proteins Regulation Reporting Repression Role Schizophrenia Shapes Signal Pathway Specificity Stimulus Synapses Synaptic plasticity Testing Transcript Translations Traumatic Brain Injury Up-Regulation age related cognitive function genome-wide analysis human DICER1 protein in vivo member nervous system disorder neurodevelopment neuronal survival neurotrophic factor new therapeutic target novel pre-miRNA prevent response synaptic function transcription factor

项目摘要

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.

描述（由申请人提供）：健康的认知功能取决于特定目标基因对传入刺激的正确调节。脑源性神经营养因子 (BDNF) 是一种神经营养蛋白，在神经元存活、分化和突触可塑性中具有明确的作用。 BDNF 可以在转录和翻译水平上调节基因表达。已知 BDNF 的多种功能，包括树突生长和长期突触可塑性，明确依赖于 BDNF 调节蛋白质合成的能力。 BDNF 通过增强翻译起始和延伸因子的活性来适度增加总神经元蛋白质合成，以全面诱导蛋白质合成机制。然而，BDNF 表现出非凡的转录特异性，并强烈上调一小部分目标的翻译，同时使某些目标不受影响并下调其他目标的翻译。这种惊人的转录选择性对于 BDNF 控制神经元蛋白质组成及其作为营养因子的作用至关重要。我们最近描绘了一条途径，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的特异性，以确定特定基因转录本是否受到抑制或增强翻译。该提案的重点是研究 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以前未知的控制基因表达特异性的机制，并为治疗与过程特别相关的脑部疾病提供潜在的新治疗靶点，例如自闭症、脆性 X 综合征、抑郁症和神经退行性疾病，其已知的联系BDNF、翻译失调或两者兼而有之。