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Targeting RNA Splicing in Glioma

胶质瘤中的靶向 RNA 剪接

基本信息

批准号：
10530184
负责人：
Shi-Yuan Cheng
金额：
$ 49.06万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10530184
关键词：
Address Affect Alternative Splicing Antisense Oligonucleotides Biological Biological Models Biological Process CDKN2A gene Cell model Classification Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA Sequence Alteration Data Set Development Disease Duchenne muscular dystrophy Eukaryota Event Evolution Genome Genotype Glioma Goals Growth Human Human Engineering Knowledge Maintenance Malignant Neoplasms Mediating Mediator of activation protein Modeling Molecular Mutation Oligonucleotides Oncogenic PTEN gene Pathway interactions Patients Phenotype Prognosis Property Protein Binding Domain Protein Isoforms Protein Splicing Proteins Proteome RNA Splicing RNA-Binding Proteins Research Research Project Grants Spliced Genes Technology Testing Therapeutic Therapeutic Intervention Transcription Process Tumor Biology Tumorigenicity Xenograft Model avatar models base clinically relevant differential expression driver mutation epidermal growth factor receptor VIII human disease induced pluripotent stem cell innovation malignant phenotype methylome molecular subtypes novel patient prognosis programs protein expression stem-like cell transcriptome transcriptome sequencing treatment response tumor tumor xenograft

项目摘要

Targeting RNA Splicing in Glioma RNA alternative splicing (AS) is an evolutionally conserved co-transcriptional process, regulates transcriptome and proteome landscapes in eukaryotes, and in human diseases such as cancer. Unlike the numerous studies that have been conducted for characterizing glioma genomes, transcriptomes, methylomes, and proteomes, little has been done to associate glioma driver mutations with AS programs and evaluate the impact of dysregulated AS on cancer malignancy. Our analyses of AS in three glioma patient RNA-seq datasets indicate two AS glioma subtypes that show associations with WHO tumor grade, glioma driver mutations, and patient prognosis. Utilizing a human induced pluripotent stem cell (hiPSC)- derived glioma “avatar” model and clinical glioma models, we show that IDH1R132H/WT or PTEN-/- /CDKN2A/2B-/-/TertpC228T/WT/EGFRvIII genotypes influence subtype-associated AS programs. Two subsets of RBPs that affect RNA splicing are differentially associated with these two AS glioma subtypes. Expression of subtype-associated RBPs or AS isoforms also affected AS events and growth of glioma stem-like cells (GSCs). In this research project, we plan to leverage our previous contributions, existing research program, recent findings, newly established glioma avatar models, cutting-edge CRISPR editing technology, and outstanding scientific premise to study whether glioma mutations influence AS programs and how RNA binding proteins (RBPs) and AS gene isoforms contribute to glioma tumor biology. AS programs will also be exploited for therapeutic intervention in treating gliomas. This project will address key gaps in our understanding of the relationships between glioma driver mutations and tumor-associated AS programs, and test whether targeting RNA splicing constitutes a therapeutic vulnerability to treat gliomas. In addressing these knowledge gaps this research will influence our understanding and treatment of glioma, and in so doing will likely influence the study of other cancers.

胶质瘤中的靶向RNA剪接 RNA选择性剪接（AS）是一种进化上保守的共转录过程，转录组和蛋白质组景观在真核生物和人类疾病，如癌症。不像已经进行了许多研究来表征神经胶质瘤基因组，转录组，甲基化组和蛋白质组，很少有人将胶质瘤驱动突变与AS程序联系起来评估AS失调对恶性肿瘤的影响。我们分析了三种胶质瘤中的AS 患者RNA-seq数据集表明两种AS胶质瘤亚型显示与WHO肿瘤分级相关，神经胶质瘤驱动突变和患者预后。利用人诱导多能干细胞（hiPSC）- 我们发现IDH 1 R132 H/WT或PTEN-/-在神经胶质瘤“化身”模型和临床神经胶质瘤模型中， /CDKN 2A/2B-/-/TertpC 228 T/WT/EGFRvIII基因型影响亚型相关AS程序两个子集影响RNA剪接的RBP与这两种AS胶质瘤亚型差异相关。亚型相关RBP或AS亚型的表达也影响AS事件和胶质瘤的生长干细胞（GSC）。在这个研究项目中，我们计划利用我们以前的贡献，现有的研究计划，最新发现，新建立的胶质瘤化身模型，尖端的CRISPR编辑技术，以及研究胶质瘤突变是否影响AS计划的杰出科学前提以及RNA结合蛋白（RBP）和AS基因亚型如何对神经胶质瘤肿瘤生物学做出贡献。作为还将开发用于治疗神经胶质瘤的治疗性干预的程序。该项目将解决我们对胶质瘤驱动突变和肿瘤相关性之间关系的理解存在关键差距。 AS程序，并测试靶向RNA剪接是否构成治疗脆弱性，以治疗神经胶质瘤在解决这些知识差距，这项研究将影响我们的理解和治疗神经胶质瘤，并在这样做可能会影响其他癌症的研究。