A Selective Approach to Metastatic Gene Discovery

转移基因发现的选择性方法

• 批准号: 6963726
• 负责人: CARLOS F BARBAS
• 金额: $ 23.24万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6963726
• 关键词: SCID mouse; athymic mouse; biotechnology; breast neoplasms; cancer prevention; gene expression; gene induction /repression; genetic mapping; genetic techniques; human tissue; immunocytochemistry; metastasis; microarray technology; neoplasm /cancer genetics; polymerase chain reaction; prognosis; protein quantitation /detection; transcription factor

DESCRIPTION (provided by applicant): This proposal seeks to develop a selective approach to metastatic gene discovery and is responsive to PA-03-100. The ability to directly select in vitro and in vivo for transcription factors that produce novel metastatic phenotypes in cancer cells is anticipated to have a significant impact on both our understanding of the cell biology of metastasis as well as the treatment of the disease. The study proposed here capitalizes on our development of designed transcription factors that enable activation or repression of endogenous genes. Polydactyl zinc finger proteins can now be prepared that recognize from 9 to 18 bp DMA target sequences with high affinity and specificity. When fused to activation or repression domains, these proteins become potent regulators of the transcriptional activity of the target genes. Currently no other gene therapy or gene tool strategy provides the means of both effectively knocking out and up-regulating the expression of an endogenous gene. This proposal focuses on the use of our transcriptional regulators to develop a new in vivo methodology for the exploration of genes involved in cell homing and metastasis in the context of the living animal. A genome-wide transcriptional modulation strategy will be developed and applied to the search for genes involved in metastasis and organ specific homing. The discovery of novel proteins key to metastasis could result in the development of a new class of cancer drugs and help to clarify the soil and seed metastasis hypothesis. With selective and potent transcriptional regulators we will address the potential of designed transcriptional regulators to prevent or otherwise alter the course of metastatic disease in animal models. The net result of this study should be an increased understanding of the cell biology of metastasis and the discovery of novel molecular targets for diagnostic, prognostic and therapeutic application.

描述（由申请人提供）：该提案旨在开发一种选择性的转移基因发现方法，并对PA-03-100做出反应。预计癌细胞中产生新型转移性表型的转录因子直接选择体内和体内的能力将对我们对转移细胞生物学以及疾病治疗的理解产生重大影响。这里提出的研究利用了我们开发设计的转录因子，这些转录因子能够激活或抑制内源基因。现在，可以准备多脱二基锌指蛋白，以识别具有高亲和力和特异性的9至18 bp DMA靶序列。当与激活或抑制域融合时，这些蛋白质成为靶基因转录活性的有效调节剂。目前，没有其他基因疗法或基因工具策略提供了有效敲除和上调内源基因表达的手段。该提案的重点是使用我们的转录调节剂来开发一种新的体内方法论，以探索活动物中涉及细胞归巢和转移的基因。将制定全基因组的转录调制策略，并将其应用于涉及转移和器官特定归纳的基因的搜索。发现新型蛋白质的转移关键可能会导致新的癌症药物的发展，并有助于阐明土壤和种子转移假设。通过选择性和有效的转录调节剂，我们将解决设计的转录调节剂的潜力，以防止或以其他方式改变动物模型中转移性疾病的过程。这项研究的最终结果应是对转移的细胞生物学的了解以及发现用于诊断，预后和治疗应用的新型分子靶标。