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

项目摘要 肺腺癌的大规模基因组调查显示， RBM 10蛋白。RBM 10突变主要由功能丧失性改变组成，这表明它可能作为一种免疫调节剂发挥作用。 肿瘤抑制基因本提案的主要目标是研究RBM 10突变在肺肿瘤中的作用。 肿瘤发生，并确定潜在的遗传依赖性特异性RBM 10缺陷型肺癌细胞。在 目的1，将Rbm 10直接靶向小鼠肺，以评估Rbm 10功能丧失在肺内的作用。 突变型KrasG 12 D诱导的肺腺癌模型。在目标2中，与RBM 10相互作用的RNA转录物 将沿着与外显子一起鉴定，所述外显子在存在或不存在 RBM10。对于目标2中的每种方法，将研究人类和小鼠癌细胞， 一组独特而强大的数据，用于识别最保守和功能相关的目标， 10.最后，在Aim 3中，将进行全基因组CRISPR/Cas9敲除筛选，以找到独特的 RBM 10突变细胞的脆弱性。拟议的研究计划将提高我们对如何 正常RNA剪接的破坏可能导致人类癌症，并可能产生新的治疗靶点。 博士Peter Choi目前是Matthew Meyerson博士实验室的博士后研究员， 丹娜-法伯癌症研究所和布罗德研究所。他的长期目标是领导一个独立的研究小组 研究基因改变如何在功能上导致人类癌症。他将执行他的 在K99期间，在肺癌领域的领导者Meyerson博士的主要指导下进行研究 基因组学额外的指导将提供一个咨询委员会组成的博士哈恩，芭比， Hammerman和Harlow将监督Choi博士的科学进步和职业发展，以及 帮助他过渡到终身教职

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.