A C. elegans model for studying blocks to EGFR signal transduction in quiescent cells

用于研究静止细胞中 EGFR 信号转导阻断的线虫模型

• 批准号: 9470061
• 负责人: Catherine Ann O'Keeffe
• 金额: $ 4.4万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-16 至 2019-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9470061
• 关键词: Alpha Cell; Animals; Biological Assay; Biosensor; Caenorhabditis elegans; Candidate Disease Gene; Cell Culture Techniques; Cell Cycle; Cell Differentiation process; Cell division; Cells; Clinical; Dangerousness; Data; Development; EGF gene; Embryonic Development; Ensure; Epidermal Growth Factor Receptor; Event; Feedback; Genetic Screening; Hormones; Human; Individual; Insulin; Interruption; Knowledge; Laboratories; Larva; Learning; Longevity; MEKKs; Maintenance; Malignant Neoplasms; Measures; Mediator of activation protein; Modeling; Nematoda; Nuclear; Organism; Pathway interactions; Phosphorylation; Phosphotransferases; RNA Interference; Ras/Raf; Receptor Signaling; Recurrence; Regulation; Reporter; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stereotyping; Study models; System; Time; Tissues; To specify; Transforming Growth Factor beta; Transgenic Organisms; Vulva; Work; adult stem cell; biological adaptation to stress; cancer cell; cancer stem cell; cancer therapy; cell type; chemotherapy; experimental study; improved; in vivo; insulin signaling; interest; multipotent cell; mutant; new therapeutic target; notch protein; novel; precursor cell; stem cell biology; stem cells; targeted agent; therapeutic target; tumor

Reversible exit from the cell cycle, or cellular quiescence, is a feature of both normal and cancer stem cells. Quiescent adult stem cells are critical for tissue maintenance and stress response. In contrast, quiescent cancer stem cells are a cause of tumor recurrence, as these cells are able to resist chemotherapy that targets actively dividing cells.Therefore, understanding basic features of stem cell biology and identifying novel therapeutic targets for quiescent cancer cells are of great clinical interest. Caenorhabditis elegans has proven to be a powerful model to investigate pathways involved in the maintenance of long term arrest. In unfavorable conditions, C. elegans larvae enter a long-lived state, known as dauer, in which cells remain quiescent and multipotent for months at a time—several times the normal lifespan of the animal. Entry into the dauer state is associated with blocks to Epidermal Growth Factor Receptor (EGFR) signal transduction. The C. elegans Vulval Precursor Cells (VPCs) have long been used to study mechanisms regulating cell fate decisions and this tractable system is subject to dauer induced arrest. This project aims to use VPCs to identify fundamental mechanisms by which conserved signaling pathways block the EGFR pathway in quiescent and multipotent cells by 1) determining the level at which EGFR signaling is regulated in dauer 2) removing putative negative regulators in order to induce VPC division and differentiation during dauer 3) using in vivo fluorescent kinase reporters to determine if stereotyped signaling dynamics characterize dauer arrest. These aims will identify crosstalk between signaling cascades and provide a model for the regulation mechanism associated with long term maintenance of quiescence.

可逆退出细胞周期或细胞静止是正常干细胞和癌症干细胞的特征。 静止的成体干细胞对于组织维持和应激反应至关重要。相比之下， 癌症干细胞是肿瘤复发的原因之一，因为这些细胞能够抵抗靶向 因此，了解干细胞生物学的基本特征， 静止癌细胞的治疗靶点具有很大的临床意义。秀丽隐杆线虫已经证明 是一个强大的模型，以调查参与维持长期逮捕的途径。在不利 条件下，C.线虫幼虫进入一种被称为Dauer的长寿状态，在这种状态下，细胞保持静止， 一次可以多活数月--是动物正常寿命的几倍。进入道尔州是 与阻断表皮生长因子受体（EGFR）信号转导相关。梭elegans 外阴前体细胞（VPC）长期以来一直用于研究调节细胞命运决定的机制， 这种易处理的系统受到Dauer诱导的阻滞。该项目旨在使用VPC来识别基本的 保守的信号通路阻断静止和多能细胞中EGFR通路的机制 通过1）确定EGFR信号传导在dauer中调节的水平，2）去除假定的阴性信号传导， 调节剂，以诱导VPC分裂和分化过程中dauer 3）使用体内荧光激酶 报道者以确定定型信号传导动力学是否表征Dauer停滞。这些目标将确定 信号级联之间的串扰，并提供了一个模型的调节机制与长 长期保持安静。