Phenotype Arrays--An approach to Novel Anticancer Target

描述：(申请人提供) 癌症研究界面临的一个重大挑战是 鉴定可提供治疗机会的蛋白质 特异性消除癌细胞。这个应用程序呈现了一个Rational 发现新的抗癌靶点的方法 合成致命性的遗传原理。目标是识别突变 它们本身是可以容忍的，但与更改不兼容 癌基因和抑癌基因中常见的，如果不是普遍的话 在癌细胞中发生改变。这样的搜索至少在技术上令人望而生畏 在哺乳动物身上。然而，方便的遗传工具和充分的 测序的基因组使模式生物成为一种有吸引力的替代物。这很好 确定果蝇是一种检测癌基因的方便模型 和肿瘤抑制通路。我们最近证明了RNA 干扰可用于去除培养的果蝇的基因表达 细胞。在此探索性应用程序中，我们建议利用 果蝇Unigene将创建一系列细胞株，其中每个基因 都被单独打乱了。每种细胞的活力 中断将在以下两种情况之一缺席和存在时进行评估 激活的RAS或RB-LOSS。仅在细胞中表现出凋亡的细胞株 癌症突变的存在将识别合成致命性 互动。这项技术的发展不仅允许 寻找抗癌靶点，但无疑也将应用于 广泛的生物学问题。

DESCRIPTION: (provided by applicant) A significant challenge facing the cancer research community is the identification of proteins that present therapeutic opportunities for the specific elimination of cancer cells. This application presents a rational approach to the discovery of novel anti-cancer targets that is based upon the genetic principle of synthetic lethality. The goal is to identify mutations which are tolerated on their own but which are incompatible with alterations in oncogenes and tumor suppressors that are commonly if not universally altered in cancer cells. Such a search is, at a minimum, technically daunting in mammals. However, the availability of facile genetic tools and fully sequenced genomes make model organisms an attractive alterative. It is well established that Drosophila is a convenient model in which to examine oncogene and tumor suppressor pathways. We have recently demonstrated that RNA interference can be used to ablate gene expression in cultured Drosophila cells. In this exploratory application, we propose to take advantage of the Drosophila unigene set to create an array of cell strains in which each gene in the set is disrupted individually. The viability of cells containing each disruption will be evaluated in the absence and in the presence of either activated ras or Rb-loss. Cell strains that show apoptosis only in the presence of the cancer mutation will identify synthetically lethal interactions. The development of this technology will allow not only allow a search for anti-cancer targets but will also undoubtedly find application to a broad range of biological problems.