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Investigating the role of RBM10-regulated alternative splicing in lung tumorigenesis

研究 RBM10 调节的选择性剪接在肺肿瘤发生中的作用

基本信息

批准号：
10083717
负责人：
Peter S. Choi
金额：
$ 24.9万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-08 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083717
关键词：
Advisory Committees Alternative Splicing CRISPR/Cas technology Cancer Etiology Cancer cell line Candidate Disease Gene Cells Cessation of life Dana-Farber Cancer Institute Data Set Dependence Development Epidermal Growth Factor Receptor Event Exons Faculty Gene Expression Genes Genetic Genetic study Genomics Goals Human In Vitro Institutes KRAS2 gene KRASG12D Knock-out Laboratories Lead Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mentorship Modeling Monitor Mus Mutation Oncogenes Pathogenesis Phenotype Positioning Attribute RNA RNA Splicing RNA-Binding Proteins Research Role Somatic Mutation Surveys Synthetic Genes Therapeutic Transcript Translating Tumor Suppressor Genes Woman base cancer cell cancer genomics career development genome-wide improved in vivo loss of function lung cancer cell lung tumorigenesis men mutant new therapeutic target novel novel therapeutic intervention tenure track

项目摘要

PROJECT SUMMARY Large-scale genomic surveys of lung adenocarcinoma have revealed frequent mutations in the RNA-binding protein RBM10. RBM10 mutations consist mainly of loss-of-function alterations, suggesting it may function as a tumor suppressor gene. The main goals of this proposal are to investigate the role of RBM10 mutations in lung tumorigenesis and to identify potential genetic dependencies specific to RBM10-deficient lung cancer cells. In Aim 1, Rbm10 will be targeted directly in the mouse lung to assess the effects of Rbm10 loss-of-function in a model of mutant KrasG12D-induced lung adenocarcinoma. In Aim 2, RNA transcripts that interact with RBM10 in lung cancer cells will be identified along with exons that are differentially spliced in the presence or absence of RBM10. For each of the approaches in Aim 2, both human and mouse cancer cells will be studied, providing a unique and powerful set of data for identifying the most conserved and functionally relevant targets of RBM10. Finally, in Aim 3, a genome-wide CRISPR/Cas9 knockout screen will be carried out to find unique vulnerabilities in RBM10 mutant cells. The proposed research plan will improve our understanding of how disruptions to normal RNA splicing can contribute to human cancer and may yield novel therapeutic targets. Dr. Peter Choi is currently a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at the Dana-Farber Cancer Institute and Broad Institute. His long-term goal is to lead an independent research group in the study of how genetic alterations are functionally responsible for human cancer. He will carry out his research during the K99 period under the primary mentorship of Dr. Meyerson, who is a leader in lung cancer genomics. Additional mentorship will be provided by an advisory committee consisting of Drs. Hahn, Barbie, Hammerman, and Harlow who will monitor Dr. Choi's scientific progress and career development, as well as help guide his transition to a tenure-track faculty position.

项目总结