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Mechanisms regulating tau alternative pre-mRNA splicing

tau 选择性前 mRNA 剪接的调节机制

基本信息

批准号：
8508774
负责人：
JANE Y WU
金额：
$ 29.54万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508774
关键词：
Address Affect Alternative Splicing Biochemical Bioinformatics Biological Biological Assay Cell Culture System Cell Death Cells Complex DNA Sequence Defect Dementia Disease Dissection Elements Enhancers Exons Frontotemporal Dementia Gene Mutation Genes Genetic Goals Human In Vitro Lead Mass Spectrum Analysis Methods Molecular Molecular Genetics Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Differentiation Neurons Pathogenesis Patients Pattern Play Proteins Proteomics Publishing RNA Interference RNA Processing RNA Splicing Reagent Regulation Regulator Genes Reporting Research Risk Factors Role Sampling Spliced Genes Structure Surveys System Tauopathies Temporal Lobe Testing Tissue Sample Trans-Activators Transcript Work base clinical phenotype crosslink expression cloning gene function mRNA Precursor nervous system disorder neuron loss neuronal survival screening stem tau Proteins tau expression tau mutation tool

项目摘要

DESCRIPTION (provided by applicant): Mechanisms regulating tau alternative pre-mRNA splicing Accumulating evidence indicates that pre-mRNA splicing defects and aberrant splicing lead to a range of neurodegenerative disorders. Alternative splicing is critical for tau gene function, and splicing mutations in the human tau gene lead to fronto-temporal lobe dementia (FTLD-tau). Although tau splicing mutations were initially reported in 1998, the mechanisms by which mutations affect tau alternative splicing are still poorly understood, and risk factors as well as genetic modifiers in FTLD-tau remain to be identified. This proposal aims to investigate the mechanisms regulating tau gene alternative splicing. We plan to use molecular, biochemical and cell biological methods to investigate tau alternative splicing and to compare the differential spliceosomal recognition of wild type versus mutant tau transcripts. We have established both in vitro biochemical assays and cell culture systems to investigate tau exon 10 alternative splicing. Using biochemical assays and an expression cloning strategy, we have identified several proteins involved in tau exon 10 alternative splicing in our preliminary studies. A primary neuronal culture system has also been set up to investigate the role of identified factors in neuronal cell death. Molecular dissection of cis- and trans-acting elements important for tau alternative splicing will not only help in understanding the basic mechanisms controlling tau alternative splicing but also reveal new players in pathogenesis of neurodegeneration. We plan to use combined bioinformatics, biochemical, molecular and genetic approaches to study the pathogenetic mechanisms underlying FTLD-tau, one most common neurodegenerative disorders.

描述（由申请人提供）：调节 tau 选择性前 mRNA 剪接的机制越来越多的证据表明前 mRNA 剪接缺陷和异常剪接会导致一系列神经退行性疾病。选择性剪接对于 tau 基因功能至关重要，人类 tau 基因的剪接突变会导致额颞叶痴呆 (FTLD-tau)。尽管 tau 剪接突变最初于 1998 年被报道，但突变影响 tau 选择性剪接的机制仍知之甚少，并且 FTLD-tau 的危险因素和遗传修饰因素仍有待确定。该提案旨在研究调节 tau 基因选择性剪接的机制。我们计划使用分子、生化和细胞生物学方法来研究 tau 选择性剪接，并比较野生型和突变型 tau 转录本的剪接体识别差异。我们建立了体外生化测定和细胞培养系统来研究 tau 外显子 10 选择性剪接。通过生化分析和表达克隆策略，我们在初步研究中鉴定了几种参与 tau 外显子 10 选择性剪接的蛋白质。还建立了原代神经元培养系统来研究已确定的因素在神经元细胞死亡中的作用。对 tau 选择性剪接重要的顺式和反式作用元件进行分子解剖不仅有助于理解控制 tau 选择性剪接的基本机制，而且还揭示了神经退行性疾病发病机制中的新参与者。我们计划结合生物信息学、生化、分子和遗传学方法来研究 FTLD-tau（一种最常见的神经退行性疾病）的发病机制。