Investigating the role of the small GTPase RIT1 in lung adenocarcinoma

研究小 GTPase RIT1 在肺腺癌中的作用

• 批准号: 9381072
• 负责人: Alice Berger
• 金额: $ 24.9万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-05 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381072
• 关键词: Advisory Committees; Apoptosis; Award; Biological; Biometry; Cancer Biology; Cancer Etiology; Cancer cell line; Cell Line; Cell model; Cells; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Dana-Farber Cancer Institute; Data; Dependency; Development; Environment; Epithelial; Epithelial Cells; Event; Fibroblasts; Funding; GTPase Gene; Gene Expression Profiling; Gene Proteins; Generations; Genetic; Genetic Epistasis; Genomics; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Histopathology; Human; In Vitro; Induced Mutation; Institutes; KRAS2 gene; Laboratories; Lead; Leadership; Lung; Lung Adenocarcinoma; Lung Neoplasms; Maintenance; Malignant Neoplasms; Mediating; Mentors; Methods; Mission; Modeling; Molecular Profiling; Monomeric GTP-Binding Proteins; Mus; Mutant Strains Mice; Mutate; Mutation; Myeloid Leukemia; Noonan Syndrome; Pathology; Phase; Phenocopy; Proteins; Proteomics; Research; Research Training; Rodent; Role; Signal Transduction; Somatic Mutation; Testing; Therapeutic; Therapeutic Intervention; Training; Tumor Suppressor Genes; Woman; Work; cancer type; candidate validation; career; career development; experimental study; gain of function mutation; human disease; in vivo; loss of function; men; metaplastic cell transformation; mortality; mouse model; mutant; mutant mouse model; public health relevance; small hairpin RNA; targeted treatment; therapeutic development; therapeutic target; tumor; tumor initiation; tumorigenesis

 DESCRIPTION (provided by applicant): Dr. Alice Berger is a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at Dana-Farber Cancer Institute and the Broad Institute. Her long-term career goal, in alignment with the mission of the NCI, is to reduce cancer-associated mortality and suffering by determining mechanisms of cancer development and identifying attractive therapeutic targets. To accomplish this goal, Dr. Berger uniquely leverages both genomics and cell biological methods to answer fundamental questions relating to cancer biology. Recently, Dr. Berger identified somatic mutations in the small GTPase gene, RIT1, in lung adenocarcinoma, one of the most prevalent and deadly cancer types in both men and women. The proposed research will test whether RIT1 mutations are required for tumor initiation and/or maintenance and will determine the critical effectors of RIT1 function in lung epithelial cells. The first aim will test the hypothesis that RIT1 is an initiating event in lung adenocarcinoma by generating a lung-specific, inducible mouse model of RIT1 mutation. To determine the mechanism of action of RIT1, the second aim will utilize unbiased quantitative proteomics and expression profiling to identify proteins/genes interacting with or regulated by RIT1 in lung epithelial cells. The third aim will determine genetic dependencies of RIT1-mutant cells using shRNA and CRISPR-mediated loss- of-function genetic experiments in tractable cellular models. Together, these studies will determine if RIT1 itself or any of its downstream effectors represent promising targets for therapeutic development in lung adenocarcinoma. The mentored phase of this award will involve establishment and analysis of in vivo and cellular models while the applicant simultaneously enhances her career development through focused biostatistics and leadership training. During the independent phase, candidate RIT1 effectors will be validated in vitro and in vivo, and the results used to apply for continued independent funding. The outstanding research environment and facilities available to Dr. Berger include laboratory space and full institutional access at both Dana-Farber Cancer Institute and the Broad Institute. Dr. Berger's research and training will be additionally enhanced by collaborations with established experts in mouse pathology, mouse modeling, and proteomics, as well as by mentoring from an advisory committee of leading cancer biologists including Dr. William Hahn, Dr. Todd Golub, Dr. Peter Hammerman, and Dr. Edward Harlow.

 描述（由申请人提供）：Alice Berger 博士是 Dana-Farber 癌症研究所和 Broad 研究所 Matthew Meyerson 博士实验室的博士后研究员。她的长期职业目标与 NCI 的使命一致，是通过确定癌症发展机制和确定有吸引力的治疗靶点来减少癌症相关的死亡率和痛苦。为了实现这一目标，伯杰博士独特地利用基因组学和细胞生物学方法来回答与癌症生物学相关的基本问题。最近，Berger 博士在肺腺癌中发现了小 GTP 酶基因 RIT1 的体细胞突变，肺腺癌是男性和女性中最常见和致命的癌症类型之一。拟议的研究将测试肿瘤发生和/或维持是否需要 RIT1 突变，并将确定肺上皮细胞中 RIT1 功能的关键效应器。第一个目标是通过生成肺特异性、可诱导的 RIT1 突变小鼠模型来检验 RIT1 是肺腺癌起始事件的假设。为了确定 RIT1 的作用机制，第二个目标将利用无偏定量蛋白质组学和表达谱来识别肺上皮细胞中与 RIT1 相互作用或受 RIT1 调节的蛋白质/基因。第三个目标是在易处理的细胞模型中使用 shRNA 和 CRISPR 介导的功能丧失遗传实验来确定 RIT1 突变细胞的遗传依赖性。总之，这些研究将确定 RIT1 本身或其任何下游效应器是否代表肺腺癌治疗开发的有希望的靶标。该奖项的指导阶段将涉及体内和细胞模型的建立和分析，而申请人同时通过重点生物统计学和领导力培训来增强其职业发展。在独立阶段，候选RIT1效应器将在体外和体内进行验证，结果用于申请持续的独立资助。 Berger 博士拥有出色的研究环境和设施，包括丹纳法伯癌症研究所和博德研究所的实验室空间和全面的机构访问权限。 Berger 博士的研究和培训将通过与小鼠病理学、小鼠建模和蛋白质组学方面的知名专家的合作以及由领先癌症生物学家（包括 William Hahn 博士、Todd Golub 博士、Peter Hammerman 博士和 Edward Harlow 博士）组成的咨询委员会的指导而得到进一步加强。