Project 2: Regulation of Pre-mRNA Splicing in Tumorigenesis

项目2：前体mRNA剪接在肿瘤发生中的调控

• 批准号: 10330424
• 负责人: Adrian R Krainer
• 金额: $ 65.04万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-10 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330424
• 关键词: 3-Dimensional; Abbreviations; Address; Alternative Splicing; Antisense Oligonucleotides; Antisense Technology; Asialoglycoprotein Receptor; Bioinformatics; Breast Epithelial Cells; Cancer Model; Cell Culture Techniques; Cellular Metabolic Process; Chemicals; Chronic Myelomonocytic Leukemia; Clinical; Computer Analysis; Data; Dependence; Dysmyelopoietic Syndromes; Dysplasia; Enhancers; Event; Exhibits; Galactosamine; Genes; Genetic; Glioblastoma; Glioma; Goals; High-Throughput RNA Sequencing; Human; Immunohistochemistry; Immunoprecipitation; Individual; Laboratories; MDM2 gene; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of liver; Mammary gland; Mass Spectrum Analysis; Mediating; Modeling; Modification; Molecular; Mus; Mutate; Mutation; Myelogenous; NCI Center for Cancer Research; Neuraxis; Normal Cell; Oncogenes; Oncogenic; Oncoproteins; Pathway interactions; Phenotype; Primary carcinoma of the liver cells; Process; Protein Isoforms; Protein Structure Initiative; Proteins; Pyruvate Kinase; RNA Processing; RNA Recognition Motif; RNA Splicing; RNA-Binding Proteins; Recurrence; Regulation; Role; Route; SRSF2 gene; Site; Somatic Mutation; Spinal Muscular Atrophy; Spliced Genes; Spliceosomes; TP53 gene; Testing; The Cancer Genome Atlas; Therapeutic; Transcriptional Regulation; Untranslated RNA; Up-Regulation; Warburg Effect; Work; acrosome stabilizing factor; aerobic glycolysis; cancer cell; cell transformation; cell type; gene function; in vivo; knock-down; mRNA Decay; mRNA Precursor; malignant breast neoplasm; mammary gland development; mouse model; overexpression; phosphorothioate; pre-clinical; receptor; repository; senescence; targeted treatment; therapeutic biomarker; therapeutic evaluation; therapeutic target; three dimensional cell culture; transcriptome sequencing; tumor; tumor growth; tumor metabolism; tumorigenesis; uptake

PROJECT SUMMARY - PROJECT 2 The central goal of Project 2 is to understand the various roles of alternative splicing in cancer, and to exploit cancer-specific features of this process to develop targeted-therapeutic approaches. Cancer cells display extensive qualitative and quantitative dysregulation of splicing, and a subset of the numerous isoforms that are inappropriately expressed contribute to tumorigenesis or altered cell metabolism. The mechanisms and pathways through which the splicing-factor oncoproteins SRSF2 and SRSF1 transform cells will continue to be investigated. Cell-culture models, as well as orthotopic and genetic mouse models will be used to study tumorigenesis promoted by these splicing factors upon mutation or overexpression in different cancer contexts, with an emphasis on recurrent mutations in myeloid dysplasias. High-throughput RNA-sequencing and computational analysis will be employed to identify and compare the splicing targets of these SR proteins in different cancer contexts, and selected targets will be characterized and manipulated to evaluate their contributions to tumorigenesis and potential as therapeutic targets or biomarkers. One key event, alternative splicing of pyruvate kinase pre-mRNA, which controls the distinctive glycolytic metabolism of cancer cells, will be thoroughly investigated as a potential therapeutic target, by specifically manipulating this process in vivo, using antisense technology and mouse models of glioma and hepatocellular carcinoma.

项目概要-项目2 项目2的中心目标是了解选择性剪接在癌症中的各种作用，并利用 这一过程的癌症特异性特征，以开发有针对性的治疗方法。癌症细胞显示 广泛的剪接的定性和定量失调，以及许多亚型的一个子集， 不适当表达有助于肿瘤发生或改变细胞代谢。的机制和 剪接因子癌蛋白SRSF 2和SRSF 1转化细胞的途径将继续受到抑制。 研究了细胞培养模型，以及原位和遗传小鼠模型将用于研究 这些剪接因子在不同癌症背景下突变或过表达时促进的肿瘤发生， 重点是骨髓发育不良中的复发性突变。高通量RNA测序和 计算分析将用于识别和比较这些SR蛋白的剪接靶点， 不同的癌症背景和选定的目标将被表征和操纵，以评估其 对肿瘤发生的贡献和作为治疗靶点或生物标志物的潜力。一个关键事件，替代 控制癌细胞独特糖酵解代谢的丙酮酸激酶前体mRNA的拼接将 作为一个潜在的治疗靶点，通过在体内特异性地操纵这一过程， 利用反义技术和胶质瘤和肝细胞癌的小鼠模型。