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LOCAL TRANSLATION IN ASTROCYTES

星形胶质细胞中的局部翻译

基本信息

批准号：
10152678
负责人：
JOSEPH D DOUGHERTY
金额：
$ 33.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152678
关键词：
3&apos Untranslated Regions Acute Address Affinity Chromatography Astrocytes Biochemical Biological Assay Brain Complement Cues Data Dendrites Dependence Disease Distal Fragile X Syndrome Generations Image In Situ Hybridization In Vitro Individual Intellectual functioning disability Learning Maintenance Measures Mediating Mediator of activation protein Memory Messenger RNA Methodology Methods Modeling Molecular Morphology Mus Neurologic Neurons Open Reading Frames Peripheral Phase Physiological Process Protein Biosynthesis Proteins Regulation Ribosomes Role Seizures Signal Transduction Slice Supporting Cell Synapses System Testing Transcript Translating Translation Process Translations Untranslated Regions Work circadian density experience extracellular imaging approach improved in vivo nervous system disorder novel postsynaptic presynaptic response transcriptome sequencing translatome

项目摘要

Dysregulation of synapses is thought to underlie a range of neurological disorders, and astrocytes are key mediators of synaptic maintenance, formation and elimination. Neurons form more synapses when co- cultured with astrocytes, and a single astrocyte may ensheath 100,000 synapses in vivo. This critical role led to the “tripartite synapse” model: the synapse is not only comprised of the presynaptic bouton and postsynaptic density but also includes a peripheral astroglial process(PAP). Like dendrites and boutons, the PAP has a specific protein composition and is remodeled morphologically in response to local activity. Extensive work has demonstrated that synaptic remodeling is regulated by local translation in neurons, particularly in the dendrite. Specific mRNAs are shuttled into dendrites where their translation can be stimulated by a variety of extracellular signals, allowing for fine-tuned regulation of local protein synthesis. Newly synthesized proteins are thought to mediate the strengthening of individual synapses that underlies learning and memory, as inhibiting translation also inhibits formation of memory. As both PAPs and dendrites are remodeled in response to activity, it is likely that both responses are essential to increasing the overall efficacy of individual synapses in response to experience. Thus a key question in the field is are astrocytes, like neurons, also able to localize specific mRNAs to their processes for translation? Here, we will address this question using biochemical approaches and functional assays to test for the enrichment and translation of specific mRNAs in the PAP. We will seek to: 1) identify the transcripts localized to astroglial ribosomes in processes, 2) determine whether features in the sequence of the transcripts themselves mediate their local translation in astrocytes, 3) determine whether molecular cues of neuronal activity are capable of stimulating local translation in astrocytes.

突触失调被认为是一系列神经系统疾病的基础，星形胶质细胞也是