CSHL Molecular Target Discovery and Development Center

CSHL分子靶点发现与开发中心

• 批准号: 7863581
• 负责人: Scott Powers
• 金额: $ 236.39万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7863581
• 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，并且将丰富的癌症基因组表征转化为临床实用性需要潜在驱动基因的功能鉴定和验证。驱动基因鉴定将导致对癌症基因型的更深入理解，创造一组重要的新生物标志物和治疗靶点，当与全基因组RNAi筛选相结合时，将导致识别关键的遗传弱点，这些弱点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，并将继续建立在此应用程序中概述的基础上。这些方法包括基于将遗传操作的祖细胞移植到受体小鼠的适当组织中的灵活小鼠模型;采用复杂的癌症基因组数据集并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;在体外和体内操纵候选靶基因表达的新RNAi技术;以及全基因组RNAi筛选以发现癌细胞的遗传弱点。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置于生物学背景中。小鼠模型中的高通量筛选将用于确定候选基因是驱动基因还是乘客基因。此外，通过识别肿瘤维持所需的驱动基因，并通过全基因组RNAi筛选来发现主要癌症基因型的可药物化漏洞，我们将发现并验证新一代癌症药物靶标。由此产生的数据，试剂和新验证的生物标志物和靶标将在TCGA网络和更广泛的癌症研究社区中公开共享，正如我们对RNAi Codex所做的那样，RNAi Codex是CSHL的短发夹RNA（shRNA）基因沉默构建体的开放访问门户/数据库。 公共卫生关系：分子靶标发现和开发中心有两个关键目标，以帮助开发癌症的新疗法。第一个目标必须是验证哪些基因突变是癌症进展的驱动因素。这些标记可能会导致治疗靶点，但这对大多数基因来说是不可能的。然而，驱动基因在诊断、预后和将治疗与癌症亚型联系起来方面具有巨大的潜力。然而，发现基因依赖性也是必要的，这些基因是特定遗传组成或组织类型癌症的有效靶点。这种依赖性有可能成为选择性靶向癌细胞而不是正常细胞的治疗靶点。