Development of An In vivo Metastasis Screen

描述（由申请人提供）：现有的工具和资源可用于开发促进体内转移的基因筛选。这种筛选将确定药物开发的新靶点，以补充目前正在开发或临床使用的治疗方法。此外，这种筛选提供的信息将有助于减少通过微阵列研究确定的潜在靶标的数量，从而表明哪些基因产物可能驱动转移。我们建议将高通量基因表达和抑制技术与体内转移方法学相结合，将体内筛选速度提高50倍。该筛查将显示蛋白质对原发肿瘤生长、体内浸润和肺部定植的作用。第一个目标将集中于产生表达或抑制选定蛋白质的细胞池。第二个目标将评估用于测量池中构造分布的检测技术。第三个目标是确定要筛选的池的适当形式。第四个和第五个目标将执行初始筛选并验证筛选中确定的候选人。此R21应用程序将使屏幕的发展和论证可行性；为评估肿瘤细胞恶性肿瘤最关键的特征-转移能力的基因功能提供了一个范例。

DESCRIPTION (provided by applicant): The tools and resources are now available for the development of screens for genes that enhance metastasis in vivo. Such screens will identify new targets for drug development that may complement therapies currently under development or in clinical use. In addition, the information provided by such screens will aid in reducing the number of potential targets that are identified through microarray studies by indicating which gene products are likely to be driving metastasis. We propose to combine high throughput gene expression and suppression technologies with in vivo metastasis methodology to accelerate in vivo screening by a factor of up to 50. The screen will indicate the contributions of proteins to the steps of primary tumor growth, intravasation, and lung colonization. The first aim will focus on production of pools of cells expressing or suppressing selected proteins. The second aim will evaluate detection technologies for measuring construct distributions in a pool. The third aim will determine the appropriate formation of pools to be screened. The fourth and fifth aims will perform an initial screen and validate candidates identified in the screen. This R21 application will enable the development of the screen and demonstrate feasibility; providing a paradigm for evaluating gene function for the most critical feature of tumor cell malignancy - the ability to metastasize. ASSESSMENT: