Identification and characterization of driver gene(s) in recurrent lung cancer am

复发性肺癌驱动基因的鉴定和表征

基本信息

批准号：
8301736
负责人：
David Mu
金额：
$ 26.54万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-08 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301736
关键词：
14q13 Address Area Biological Assay Candidate Disease Gene Clinical Collaborations DNA copy number Data Data Set Diagnosis Diagnostic Epithelial Cells Evaluation Future Gene Expression Genes Genome Genomics Gleevec Goals Growth In Vitro KRAS2 gene Laboratories Libraries Lung Malignant Neoplasms Malignant neoplasm of lung Methods Molecular Oligonucleotides Oncogenes RNA Interference RNA library Recurrence Representational Oligonucleotide Microarray Analysis Research Research Personnel Research Proposals Resolution Roche brand of trastuzumab Sampling Squamous cell carcinoma Technology Tumorigenicity Work base cancer cell design follow-up gain of function gene function genome-wide in vivo insight loss of function lung carcinogenesis new therapeutic target novel overexpression prognostic success therapeutic target tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): We have completed analysis of over 250 lung cancer samples by a high- resolution genome profiling method developed here at Cold Spring Harbor Laboratory (CSHL). We found twelve major recurrent amplicons, most of which contain known driver genes such as MYC or KRAS2, and three others that do not, including the second most frequent amplicon which is located at 14q13. Our first specific aim is to perform comprehensive functional evaluation of all three candidate driver genes within this frequently amplified region at 14q13. This comprehensive functional evaluation will utilize both gain-of-function transformation assays and loss-of-function assays using new RNA interference technology, developed here at CSHL, that silences gene expression in vitro and in vivo. We have preliminary data that indicates that all three genes, each encoding a different transcription factors, synergistically promote the proliferation of lung epithelial cells. In addition to functional analysis, we have formed collaborations to address the potential diagnostic and prognostic significance of 14q13 amplification. The other two novel frequent amplicons contain several candidate genes. To address the difficulty inherent in functional analysis of amplicons containing many overexpressed genes, our second specific aim is to develop new barcoded RNA library interference technology, which enables functional analysis of many genes in parallel, into a robust tool for functional analysis of amplicons with large numbers of candidate driver genes. Our results will produce new insights into the molecular basis of lung carcinogenesis and should identify key therapeutic targets and new strategies for diagnostics for this highly lethal cancer. The first goal of this study focuses on the discovery and functional characterization of novel causal genes of one of the most deadly forms of lung cancer. The second goal is to create a gene function-based tool to enable researchers to rapidly identify the causal gene within a recurrent amplified genomic region that contains too many genes to be studied by a gene-by-gene approach. Forward research progress of this research proposal is expected to positively impact the diagnosis and treatment of lung cancer in the future. The first goal of this study focuses on the discovery and functional characterization of novel causal genes of one of the most deadly forms of cancers ¿ lung cancer. The second goal is to create a gene function-based tool to enable researchers to rapidly identify the causal gene within a recurrent amplified genomic region that contains too many genes to be studied by a gene-by-gene approach. Forward research progress of this research proposal is expected to positively impact the diagnosis and treatment of lung cancer in the future.

描述（由适用提供）：我们通过在冷泉港实验室（CSHL）上开发的高分辨率基因组分析方法（CSHL）完成了250多种肺癌样品的分析。我们发现了十二个主要的复发器放大器，其中大多数包含已知的驱动基因，例如MYC或KRAS2，还有其他三个没有，包括位于14Q113的第二次最频繁的扩增子。我们的第一个具体目的是在2013年第14季度在这个经常扩展的区域内对所有三个候选驱动器基因进行全面的功能评估。这种全面的功能评估将利用功能获得的转化分析和使用新的RNA干扰技术的功能转换测定和功能丧失评估，该技术在CSHL上开发，在体外和体内沉默了基因表达。我们有初步数据，表明所有三个基因（每个基因均编码不同的转录因子）协同促进肺上皮细胞的增殖。除了功能分析外，我们还成立了协作，以解决14Q13扩增的潜在诊断和预后意义。其他两个新颖的扩增经常包含几个候选基因。为了解决包含许多过表达基因的放大的功能分析的固有的困难，我们的第二个特定目的是开发新的条形码RNA库干扰技术，该技术可以将许多基因的功能分析成为一种可行的工具，以用于对具有大量候选驱动器基因的扩增子的功能分析。我们的结果将对肺癌发生的分子基础产生新的见解，并应确定这种高度致命癌症的诊断剂的关键治疗靶标和新策略。这项研究的第一个目标集中于最致命形式的肺癌之一的新因果基因的发现和功能表征。第二个目标是创建一个基于基因功能的工具，以使研究人员能够在复发的放大基因组区域中迅速识别催化基因，该基因组包含过多基因，无法通过基因by-Gene方法研究。预计将来该研究建议的远期研究进度将对肺癌的诊断和治疗产生积极影响。这项研究的第一个目标侧重于发现和功能表征最致命的癌症形式之一肺癌的新型因果基因。这第二个目标是创建一个基于基因功能的工具，以使研究人员能够快速确定也包含的复发性扩增基因组中的因果基因通过基因方法进行研究的许多基因。远期研究进度预计该研究建议将对诊断和治疗产生积极影响将来的肺癌。