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

基本信息

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
项目类别：
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&apos 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

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. 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响应传入刺激的特定靶向基因的正确调节。脑衍生的神经营养因子（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良好的作用。 BDNF可以调节转录和翻译水平的基因表达。已知BDNF的几种功能，包括树突状产生和长期突触可塑性，明确取决于BDNF调节蛋白质合成的能力。 BDNF通过增强翻译起始和伸长因子的活性来适度增加总神经元蛋白的合成，从而在全球范围内诱导蛋白质合成机制。但是，BDNF表现出了非凡程度的转录本特异性，并强烈上调了一小部分目标的翻译，同时使某些目标不受影响并下调了其他目标。这种惊人的转录本选择性对于BDNF及其作为营养因子的作用对神经元蛋白组成的控制至关重要。最近，我们描述了一条途径，通过该途径，BDNF通过正面和负调节成熟miRNA的生物发生来控制蛋白质合成中的特异性，以确定特定基因转录本是否受到抑制或经历增强的翻译。该建议的重点是检查BDNF控制miRNA生物发生，该调节的空间和时间方面以及这些新型途径成分在认知功能中的作用的分子机制。我们研究的结果WIL揭示了以前未知的机制控制基因表达的特异性，并为治疗与过程特别相关的脑疾病提供了潜在的新治疗靶点，例如自闭症，脆弱的X综合征，抑郁症和神经退行性疾病，具有与BDNF的已知联系，与BDNF，bdnf，不良转化的翻译或两者。公共卫生相关性：动物模型中BDNF信号通路的失调既会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有关，包括记忆力障碍，自闭症，精神分裂症，精神分裂症和强迫症。增强BDNF表达可以减轻与多种神经系统疾病有关的认知缺陷，包括阿尔茨海默氏病，抑郁症，脑外伤和与年龄有关的痴呆。我们的建议将揭示新的机制和潜在的新治疗靶标，该靶标在BDNF的下游运行以确定其对神经元蛋白质组的影响。