Neurology and the molecular role of N-RBPs in the brain

神经病学和 N-RBP 在大脑中的分子作用

基本信息

批准号：
9128723
负责人：
ROBERT B DARNELL
金额：
$ 12.44万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-09-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9128723
关键词：
Acute Address Adult Age Amyotrophic Lateral Sclerosis Area Binding Binding Sites Brain Brain Diseases Carotid Arteries Cells Chronic stress Data Diagnostic Disease Epilepsy Epitopes Funding Gene Expression Generations Genomic DNA Health Hippocampus (Brain)Human In Vitro Individual Investigation Ischemia Knockout Mice LoxP-flanked allele Maps Mediating Methods MicroRNAs Modeling Molecular Motor Neuron Disease Motor Neurons Mus Neurodegenerative Disorders Neurologic Neurology Neurons Pathogenesis Plant Roots Play Protein Biosynthesis Proteins RNA RNA-Binding Proteins Regulation Role Seizures Spinal Spinal Cord Stress System Time Transcript Untranslated Regions Variant artery occlusion cell type combinatorial crosslinking and immunoprecipitation sequencing genome-wide homologous recombination human disease in vivo insight mind control mouse model new technology research study stoichiometry therapeutic development tool transcriptome sequencing

Acute Address Adult Age Amyotrophic Lateral Sclerosis Area Binding Binding Sites Brain Brain Diseases Carotid Arteries Cells Chronic stress Data Diagnostic Disease Epilepsy Epitopes Funding Gene Expression Generations Genomic DNA Health Hippocampus (Brain)Human In Vitro Individual Investigation Ischemia Knockout Mice LoxP-flanked allele Maps Mediating Methods MicroRNAs Modeling Molecular Motor Neuron Disease Motor Neurons Mus Neurodegenerative Disorders Neurologic Neurology Neurons Pathogenesis Plant Roots Play Protein Biosynthesis Proteins RNA RNA-Binding Proteins Regulation Role Seizures Spinal Spinal Cord Stress System Time Transcript Untranslated Regions Variant artery occlusion cell type combinatorial crosslinking and immunoprecipitation sequencing genome-wide homologous recombination human disease in vivo insight mind control mouse model new technology research study stoichiometry therapeutic development tool transcriptome sequencing

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项目摘要

DESCRIPTION (provided by applicant): We propose to identify functional interactions between Ago-miRNA and neuron-specific RNA binding proteins (nRNABPs) in the normal and stressed mouse brain. RNA regulation in vivo involves the superimposed and likely combinatorial action of many RNABPs, but most investigations of RNABPs have focused on the role of individual proteins in vitro. This has confined our understanding of "conventional" regulation by RNABPs and how they intersect with Argonaute (Ago) mediated miRNA regulation; while it is suspected that these two systems intersect, there is almost no understanding of where they do so or what the functional consequences are. The expanding list of RNABPs and miRNAs associated with neurologic disease has underscored large gaps in our understanding of their roles in disease pathogenesis. We developed HITS-CLIP during the last funding period, a revolutionary approach to the study of protein-RNA regulation, and will apply it for the first time to studying coordinate and dynamic regulation by Ago-miRNA and neuronal RNABPs. These studies will be applied to normal brain, using homologous recombination in mice to establish robust and relevant in vivo study in neurons. They will then be applied to stress brain, using three brain-disease relevant paradigms.

描述（由申请人提供）：我们建议在正常和应力的小鼠脑中确定AGO-MIRNA和神经元特异性RNA结合蛋白（NRNABP）之间的功能相互作用。 RNA在体内调节涉及许多RNABP的叠加且可能的组合作用，但是大多数RNABP的研究都集中在单个蛋白质在体外的作用。这限制了我们对RNABPS的“常规”调节的理解，以及它们如何与Argonaute（AGO）介导的miRNA调节相交。虽然怀疑这两个系统相交，但几乎不了解它们在哪里或功能后果是什么。与神经系统疾病相关的RNABP和miRNA的扩大清单突显了我们对它们在疾病发病机理中作用的理解。我们在最后一个资金期间开发了hits-clip，这是一种革命性的蛋白质-RNA调控方法，并将首次将其应用于AGO-MIRNA和神经元RNABPS的坐标和动态调节。这些研究将使用小鼠中的同源重组来应用于正常的大脑，以在神经元中建立鲁棒和相关的体内研究。然后，使用三个脑疾病相关的范例将它们应用于压力大脑。