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Using proteogenomics to assess the functional impact of alternative splicing events in glioblastoma

使用蛋白质基因组学评估选择性剪接事件对胶质母细胞瘤的功能影响

基本信息

批准号：
10577186
负责人：
CHARLES S COBBS
金额：
$ 20.7万
依托单位：
SWEDISH MEDICAL CENTER, FIRST HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10577186
关键词：
Affect Alternative Splicing Apoptosis Awareness Biological Biological Assay Biological Process Biopsy Biopsy Specimen Brain Brain Neoplasms Cell Separation Data Development Event Excision Exons Future Genes Genetic Transcription Glioblastoma Glioma Goals Growth Invaded Investigation Malignant - descriptor Malignant Neoplasms Mass Spectrum Analysis Methodology Methods Molecular Molecular Analysis Molecular Weight Normal tissue morphology Operative Surgical Procedures Pathogenesis Pathway interactions Patients Pattern Process Prognosis Protein Isoforms Proteins Proteomics RNA RNA Splicing Radiation therapy Research Resolution Reverse Transcriptase Polymerase Chain Reaction Sampling Source Spliced Genes Survival Rate Techniques Technology Testing Time Tissues Transcript Tumor Antigens Validation Variant Western Blotting Work biobank cancer survival cancer type candidate identification chemotherapy diagnostic biomarker differential expression experimental study follow-up large scale data mRNA sequencing neoplastic cell new therapeutic target novel novel marker novel strategies personalized medicine potential biomarker precision medicine protein folding proteogenomics public database side effect small hairpin RNA standard of care stem cells therapeutic target transcriptome sequencing transcriptomics translational study tumor tumor initiation variant detection

项目摘要

PROJECT ABSTRACT Glioblastoma (GBM) is the most malignant type of brain tumor, with a median survival time of 15 months. Despite advances in cancer survival for many malignancies, GBM survival rates still remain low and have not significantly changed over the last 30 years, emphasizing the urgent need for new treatment options. One of the common hallmarks of cancer is splicing perturbations and alternatively spliced genes are an interesting new source for potential diagnostic biomarkers and therapeutic targets. Current methodologies to characterize splicing in tumors using mRNA sequencing can only indicate that alternative exons are transcribed, but additional validation is needed to verify that these spliceforms produce functional proteins. Our preliminary results comparing paired tumor/normal samples indicate that alternative splicing in GBM affects many more genes than previously expected, both at the transcript and protein levels. Based on these data, we hypothesize that a set of alternatively spliced genes are involved in tumor initiation and GBM pathogenesis. In this proposal, we will use a combination of precision medicine approaches to detect and quantify tumor-specific alternative splicing events in GBMs. We will verify that these events produce distinct proteoforms using splicing-aware proteogenomics experiments. Finally, we will functionally characterize differentially expressed splice isoform candidates for their effects on growth, apoptosis, and invasion in patient-derived glioma stem cells. If successful, this work will lead to new understanding of the biological impact of novel GBM proteoforms, and potentially lead to novel approaches to treatment of GBM based on unique tumor antigens and molecular pathways.

项目摘要