A Cancer Rainbow Mouse for Simultaneous Assessment of Multiple Oncogenes

用于同时评估多种癌基因的癌症彩虹小鼠

• 批准号: 8810815
• 负责人: Marc G. Caron
• 金额: $ 39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-09 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8810815
• 关键词: Adult; Advanced Development; Behavior; Brain; Breeding; Cells; Cloning; Communities; Data; Development; Diagnosis; Emerging Technologies; Engineering; Enhancers; Ensure; Failure; Felis catus; Funding; Future; Generations; Genes; Genetic Code; Genetically Engineered Mouse; Genomics; Heart; Human Genome Project; Image; Intestines; Kidney; Laboratories; Life; Liver; Location; Lung; Malignant Neoplasms; Mediating; Messenger RNA; Methodology; Mining; Modeling; Molecular; Molecular Target; Monitor; Mouse Strains; Mus; Mutation; Neoplasm Metastasis; Oncogene Activation; Oncogenes; Pancreas; Performance; Phase; Positioning Attribute; Protein Isoforms; Proteins; Reporter; Research; Research Personnel; Resolution; Risk; Role; Seasons; Skin; Solutions; Specificity; Stem cells; System; Technology; Testing; Testis; Therapeutic Intervention; Thinking; Time; Tissues; Transgenes; Translating; Tumor Burden; anticancer research; base; cancer prevention; cancer therapy; cell behavior; cell type; cellular targeting; comparative; cost effective; deep sequencing; design; flexibility; gene function; genome editing; in vivo; innovation; meetings; migration; model development; mouse model; next generation; personalized therapeutic; programs; prospective; public health relevance; recombinase; research study; success; tool; tumor; tumor initiation; tumorigenesis; tumorigenic; vector

 DESCRIPTION (provided by applicant): A Cancer rainbow mouse for simultaneous assessment of multiple oncogenes Genetically engineered mouse models of cancer hold significant promise for studying the basic cellular and molecular mechanisms underlying tumor formation and then evaluating prospective therapies. However, several factors have limited the success of current models and development of next-generation technologies. First, the conceptualization, engineering, and generation of a new mouse strain is outside the scope of most laboratories. These projects encounter high rates of failure and continue to carry significant risk for even the most seasoned and prestigious research programs. Second, establishing roles for tumor driver genes in vivo in important cellular behaviors such as differentiation, proliferation, and migration often requires extensive compound breeding, making these experiments expensive and time consuming. Third, deep-sequencing continues to identify new tumor driver genes at a rate in which the utilization of a one driver gene per mouse paradigm is unable to keep pace. Therefore to meet these demanding needs, we have developed the Cancer rainbow (Crainbow) mouse platform to generate user-defined, reliable, and multiplexed models of tumorigenesis in a single genetically tractable system. In our R21 IMAT funded project, we have demonstrated in vivo proof-of-principle for this technology and are now beyond the initial phases of this project. With this system we are able to stochastically express multiple tumor driver genes in a diversity of tissues and cell-types and simultaneously monitor their effects at a single cell level using spectrally resolvable fluorescent protein reporters. The objective of this R33 proposal is to perform extensive and rigorous testing of our emerging technology to ensure its reliability and accessibility for the scientific community. To achieve this objective, our specific aims will 1) Optimize Crainbow Generation and Expression, 2) Validate Crainbow technology In Vivo, and 3) Validate Quantitative Multiplex Analysis of Driver Gene Activity In Vivo. We expect the Crainbow platform to transform cancer research by enabling all investigators to reliably build mouse models of cancer on-demand and with minimal inherent risk. The flexible and forward-thinking design of Crainbow will also enable robust delivery of genome-editing tools to provide multiplexing of endogenously edited driver genes with cellular and temporally precise resolution. Through multiplex driver gene analysis and enabling of a decentralized user-base, the Crainbow platform will enable synergistic modeling of a diversity of cancers and provide future models for testing personalized therapeutic intervention.

 描述（由申请人提供）：用于同时评估多种癌基因的癌症彩虹小鼠基因工程小鼠癌症模型对于研究肿瘤形成的基本细胞和分子机制以及随后评估前瞻性疗法具有重要前景。首先，新小鼠品系的概念化、工程化和生成超出了大多数实验室的范围，这些项目的失败率很高，并且即使对于普通人来说也仍然存在重大风险。最有经验的其次，确定肿瘤驱动基因在体内重要细胞行为（例如分化、增殖和迁移）中的作用通常需要大量的化合物育种，这使得这些实验既昂贵又耗时。第三，深度测序不断发现新的。驱动肿瘤基因的速度是每个小鼠使用一个驱动基因的范例无法跟上的，因此，为了满足这些苛刻的需求，我们开发了癌症彩虹（Crainbow）小鼠平台来生成用户定义的、可靠的、和单一肿瘤发生的多重模型在我们的 R21 IMAT 资助的项目中，我们已经证明了该技术的体内原理验证，并且现在已经超出了该项目的初始阶段，通过该系统，我们能够在一个基因中随机表达多个肿瘤驱动基因。 R33 提案的目的是对我们的新兴技术进行广泛而严格的测试，以确保其可靠性和可访问性。为了实现这一目标，我们的具体目标是 1) 优化 Crainbow 的生成和表达，2) 验证体内 Crainbow 技术，以及 3) 验证体内驱动基因活性的定量多重分析 我们预计 Crainbow 平台将发生转变。 Crainbow 的灵活和前瞻性设计也将使所有研究人员能够按需可靠地构建癌症小鼠模型，并以最小的固有风险进行癌症研究。基因组编辑工具可提供具有细胞和时间精确分辨率的内源性编辑驱动基因的多重分析，并支持分散的用户群，Crainbow 平台将能够对多种癌症进行协同建模，并提供未来的模型。测试个性化治疗干预。