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: 9113528
• 负责人: Alice Berger
• 金额: $ 2.26万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9113528
• 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; Health; Histopathology; Human; In Vitro; 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; gain of function mutation; human disease; in vivo; loss of function; men; metaplastic cell transformation; mortality; mouse model; mutant; mutant mouse model; research study; 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（由适用提供）：Alice Berger博士是Dana-Farber Cancer Institute和Broad Institute的Matthew Meyerson博士实验室的博士后研究员。她的长期职业目标与NCI的任务保持一致，是通过确定癌症发展的机制并确定有吸引力的治疗靶标，以减少与癌症相关的死亡率和痛苦。为了实现这一目标，Berger博士唯一利用基因组学和细胞生物学方法来回答与癌症生物学有关的基本问题。最近，Berger博士在肺腺癌的小GTPase基因RIT1中鉴定了体细胞突变，这是男性和女性中最普遍，最致命的癌症类型之一。拟议的研究将测试肿瘤倡议和/或维持是否需要RIT1突变，并确定RIT1功能在肺上皮细胞中的关键作用。第一个目的将检验以下假设：RIT1是通过产生RIT1突变的肺特异性小鼠模型，是肺腺癌中的起始事件。为了确定RIT1的作用机理，第二个目标将利用无偏的定量蛋白质组学和表达分析来识别与肺上皮细胞中RIT1相互作用或调节的蛋白质/基因。 SHRNA和CRISPR介导的功能丧失基因实验在可牵引的细胞模型中。总之，这些研究将确定RIT1本身或其任何下游效应是否代表了肺腺癌治疗发展靶标。该奖项的重要阶段将涉及对体内和蜂窝模型的建立和分析，而适当的简单阶段可以通过集中的生物统计学和领导培训来增强她的职业发展。在独立阶段，候选RIT1效应将在体外和体内进行验证，并用于申请持续独立资金的结果。 Berger博士可用的杰出研究环境和设施包括实验室空间和Dana-Farber癌症研究所和Broad Institute的全部机构通道。贝尔格博士的研究和培训将通过与老鼠病理学，老鼠建模和蛋白质组学领域的既定专家以及包括威廉·哈恩（William Hahn）博士，托德·戈鲁布（Todd Golub）博士，彼得·哈默曼（Peter Hammerman）博士和爱德华·哈洛（Edward Harlow）的咨询委员会的心理委员会进行合作，并通过培训的研究和培训。