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 生物合成和特异性

• 批准号: 8344656
• 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: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8344656
• 关键词: Accounting; Adult; Alzheimer' s Disease; Animal Model; Autistic Disorder; Binding; Binding Sites; Biogenesis; Biological Models; Brain; Brain Diseases; Brain-Derived Neurotrophic Factor; Cells; Chromatin; Cognitive; 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 association study; 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

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. PUBLIC HEALTH RELEVANCE: Dysregulation of BDNF signaling pathways in animal models produces both neurodevelopment and cognitive defects, while human gene polymorphisms in BDNF have been associated with neurocognitive defects including memory deficits, autism, schizophrenia, and obsessive-compulsive disorders. Enhancing BDNF expression can mitigate cognitive defects associated with a variety of neurological disorders, including Alzheimer's disease, depression, brain trauma, and age-related dementia. Our proposal will reveal novel mechanisms, and potential new therapeutic targets, which operate downstream of BDNF to determine its effects on the neuronal proteome.

描述（由申请人提供）：健康的认知功能取决于特定靶基因对传入刺激的正确调节。脑源性神经营养因子（BDNF）是一种神经营养因子，在神经元的存活、分化和突触可塑性中具有公认的作用。BDNF可以在转录和翻译水平上调节基因表达。已知BDNF的几种功能，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通过增强翻译起始因子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表现出非凡程度的转录特异性，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并下调其他靶标的翻译。这种显著的转录选择性对于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。我们最近描绘了一条通路，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物是否被抑制或进行增强的翻译。该建议的重点是研究BDNF控制miRNA生物合成的分子机制，这种调节的空间和时间方面，以及这些新的通路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，已知与BDNF，失调翻译或两者有关。 公共卫生相关性：在动物模型中，BDNF信号通路的失调产生神经发育和认知缺陷，而BDNF中的人类基因多态性与神经认知缺陷相关，包括记忆缺陷、自闭症、精神分裂症和强迫症。增强BDNF表达可以减轻与各种神经系统疾病相关的认知缺陷，包括阿尔茨海默病，抑郁症，脑创伤和年龄相关性痴呆。我们的建议将揭示新的机制，和潜在的新的治疗靶点，其运作的BDNF下游，以确定其对神经元蛋白质组的影响。