The role and mechanism of alternative RNA splice variants and gene fusions as drivers of cancer

替代RNA剪接变体和基因融合作为癌症驱动因素的作用和机制

基本信息

批准号：
10689283
负责人：
ERIC C. HOLLAND
金额：
$ 83.99万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689283
关键词：
Address Adult Alternative Splicing Big Data Biological Models Biology Brain Neoplasms Clinical Data Data Analyses Development Diagnostic Disease Embryo Embryonic Development Ependymoma FDA approved Gene Fusion Genetically Engineered Mouse Genomics Glioma Grant Human Laboratories Malignant Neoplasms Microtus Modeling Molecular Mus Patients Pharmaceutical Preparations Population RNA Splicing Role Technology Testing Therapeutic Therapeutic Studies Tissues Variant Visualization software Work human data improved large datasets meningioma mouse model rare cancer therapeutic target treatment response tumor tumorigenesis

Address Adult Alternative Splicing Big Data Biological Models Biology Brain Neoplasms Clinical Data Data Analyses Development Diagnostic Disease Embryo Embryonic Development Ependymoma FDA approved Gene Fusion Genetically Engineered Mouse Genomics Glioma Grant Human Laboratories Malignant Neoplasms Microtus Modeling Molecular Mus Patients Pharmaceutical Preparations Population RNA Splicing Role Technology Testing Therapeutic Therapeutic Studies Tissues Variant Visualization software Work human data improved large datasets meningioma mouse model rare cancer therapeutic target treatment response tumor tumorigenesis

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项目摘要

Abstract My lab has been the leader in the field of mouse modeling for brain tumors over the past 15 years. We have developed a suite of genetically engineered mouse models that are demonstrably representative of human gliomas and other tumor types. These models have been used to inform treatment options for clinical agents, and this now enables us to propose these models are suitable testbeds for testing potential major improvements to how these diseases are treated. We have three projects. 1) We are understanding the central role of specific splice variants of TrkB in embryonic development and oncogenesis throughout the body. The RCAS modeling system has been used here to show that forced expression of the embryonic splice variant in adult tissues leads to cancer formation broadly. In this project we will investigate the mechanisms of oncogenesis for this splice variant and determine if it could be a good diagnostic or therapeutic target. 2) We are now using the modeling system developed for glioma to address the biology of rare tumors driven by gene fusions. In this grant we propose to understand the mechanisms of oncogenesis for YAP1 gene fusions in the rare tumors ependymoma, porocarcinoma and aggressive meningioma (all for which we have YAP1 gene fusion driven models currently). 3) And, we will use these mouse models to study therapeutic response and identify therapeutic strategies for these fusion driven tumors including identification of FDA approved drugs that would intervene downstream of the action of the gene fusion.

抽象的在过去的15年中，我的实验室一直是脑肿瘤小鼠建模领域的领导者。我们有开发了一套基因工程的小鼠模型，这些模型明显地代表了人类神经胶质瘤和其他肿瘤类型。这些模型已用于为临床药物的治疗选择提供信息，现在，这使我们能够提出这些模型是合适的测试床，用于测试潜在的重大改进这些疾病如何治疗。我们有三个项目。 1）我们了解特定的核心作用 TRKB在胚胎发育和整个体内肿瘤发生中的剪接变体。 RCAS建模系统已被用来表明成人组织中胚胎剪接变体的强迫表达广泛导致癌症形成。在这个项目中，我们将研究肿瘤发生的机制剪接变体，并确定它是否可能是一个良好的诊断或治疗靶点。 2）我们现在正在使用为神经胶质瘤开发的建模系统旨在解决由基因融合驱动的稀有肿瘤的生物学。在这个授予我们建议了解稀有肿瘤中YAP1基因融合的肿瘤发生机制膜瘤，毛car瘤和侵袭性脑膜瘤（我们为其YAP1基因融合驱动当前模型）。 3），我们将使用这些鼠标模型研究治疗反应并确定这些融合驱动的肿瘤的治疗策略，包括鉴定FDA批准的药物干预基因融合的作用。