CSHL Molecular Target Discovery and Development Center

CSHL分子靶点发现与开发中心

• 批准号: 7944129
• 负责人: Scott Powers
• 金额: $ 237.4万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7944129
• 关键词: Address; Antibodies; Antineoplastic Agents; Atlases; Behavior; Bioinformatics; Biological; Biological Markers; Candidate Disease Gene; Cataloging; Catalogs; Clinical; Collaborations; Communities; Complex; Data; Data Set; Databases; Dependency; Development; Diagnosis; Drug Delivery Systems; Gene Mutation; Gene Silencing; Gene Targeting; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Heterogeneity; Histocompatibility Testing; Human; In Vitro; Laboratories; Lead; Link; Maintenance; Malignant Neoplasms; Methods; Molecular Target; Mus; Normal Cell; Outcome; Pathway interactions; Publishing; RNA Interference; Ramp; Reagent; Research Personnel; Role; Stem cells; Technology; Testing; Tissue Microarray; Tissues; Translating; Transplantation; Validation; anticancer research; base; cancer cell; cancer genome; cancer therapy; cancer type; flexibility; functional genomics; gene discovery; genome-wide; high throughput screening; in vivo; innovation; interest; mouse model; novel; outcome forecast; practical application; public health relevance; response; skills; small hairpin RNA; therapeutic development; therapeutic target; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): In this application we describe our plans to create a Molecular Target Discovery and Development Center (MTDDC) that will act as downstream component of The Cancer Genome Atlas (TCGA) project. Our premise is that the complexity of cancer genome alterations leads directly to the heterogeneity of cancer behavior and outcome, and that to translate the wealth of cancer genome characterization into clinical utility requires the functional identification and validation of the underlying driver genes. Driver gene identification will lead to a deeper understanding of cancer genotypes, create an important new set of biomarkers and therapeutic targets, and when combined with genome-wide RNAi screens, lead to the identification of key genetic vulnerabilities that will serve as a new generation of therapeutic targets. Our planned center is a natural expansion of long- standing collaborative projects at Cold Spring Harbor Laboratory (CSHL) and combines several powerful methods that we have developed and will continue to build upon as outlined in this application. These methods include flexible mouse models based on the transplantation of genetically-manipulated progenitor cells into the appropriate tissues of recipient mice; novel bioinformatics that take complex cancer genome datasets and pinpoint candidate driver genes and considerably altered pathways; new RNAi technology to manipulate the expression of candidate target genes in vitro and in vivo; and genome-wide RNAi screens to find genetic vulnerabilities of cancer cells. The CSHL MTDDC will use these innovative tools to place the complex array of genomic alterations identified by cancer genome projects into biologic context. High-throughput screening in mouse models will be used to determine whether candidate genes are drivers or passengers. Additionally, through the identification of those driver genes that are required for tumor maintenance and by genome-wide RNAi screens to find the druggable vulnerabilities of major cancer genotypes, we will discover and validate a new generation of cancer drug targets. The resultant data, reagents, and newly validated biomarkers and targets will be openly shared among the TCGA network and broader cancer research communities, as we have done with RNAi Codex, CSHL's open-access portal/database for short-hairpin RNA (shRNA) gene-silencing constructs. PUBLIC HEALTH RELEVANCE: There are two critical goals for Molecular Target Discovery and Development Centers to make towards helping develop new treatments for cancer. The first goal must be to validate which of the gene mutations is a driver for cancer progression. These markers may lead to therapeutic targets, but this is unlikely for most genes. However the driver genes have great potential for diagnosis, prognosis and linking therapies to cancer subtypes. It is also necessary, however, to discover gene dependencies, the genes that are validated targets for cancers of specific genetic make up or tissue type. Such dependencies have the potential to become therapeutic targets that will selective target cancer cells versus normal cells.

描述（由申请人提供）：在本申请中，我们描述了我们创建分子靶标发现和开发中心（MTDDC）的计划，该中心将作为癌症基因组图谱（TCGA）项目的下游组成部分。我们的前提是，癌症基因组改变的复杂性直接导致癌症行为和结果的异质性，并且将癌症基因组表征的财富转化为临床应用需要对潜在驱动基因的功能识别和验证。驱动基因鉴定将导致对癌症基因型的更深入了解，创造一套重要的新生物标志物和治疗靶点，并与全基因组RNAi筛选相结合，导致关键遗传脆弱性的鉴定，将作为新一代的治疗靶点。我们计划的中心是冷泉港实验室（CSHL）长期合作项目的自然扩展，并结合了我们已经开发的几种强大的方法，并将继续建立在本申请中概述的基础上。这些方法包括基于将基因操纵的祖细胞移植到受体小鼠的适当组织中的柔性小鼠模型；采用复杂的癌症基因组数据集和精确定位候选驱动基因和显著改变的途径的新型生物信息学；新的RNAi技术在体外和体内操纵候选靶基因的表达；以及全基因组RNAi筛选，以发现癌细胞的遗传脆弱性。CSHL MTDDC将使用这些创新工具将癌症基因组计划识别的复杂基因组改变序列置于生物学背景下。小鼠模型中的高通量筛选将用于确定候选基因是驱动者还是乘客。此外，通过鉴定肿瘤维持所需的驱动基因，并通过全基因组RNAi筛选发现主要癌症基因型的可药物脆弱性，我们将发现并验证新一代癌症药物靶点。由此产生的数据、试剂、新验证的生物标志物和靶点将在TCGA网络和更广泛的癌症研究社区之间公开共享，正如我们对RNAi Codex所做的那样，RNAi Codex是CSHL的短发夹RNA （shRNA）基因沉默构建物的开放访问门户/数据库。