COBRE PROJ 9: STRUCTURE-ACTIVITY ANALYSIS OF TISSUE-SPECIFIC CARCINOGENS

COBRE 项目 9：组织特异性致癌物的结构活性分析

• 批准号: 8167782
• 负责人: ALBERT R CUNNINGHAM
• 金额: $ 23.99万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167782
• 关键词: Biological; Biological Assay; Carcinogens; Cell Line; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Experimental Models; Funding; Genome; Grant; Institution; Libraries; Ligands; Methods; Modeling; Molecular Models; Molecular Target; Proteome; Proteomics; Research; Research Personnel; Resources; Rodent Model; Site; Source; Structure; Structure-Activity Relationship; Tissues; Toxicogenomics; United States National Institutes of Health; Update; base; carcinogenesis; carcinogenicity; chemical carcinogen; chemical carcinogenesis; comparative; in vitro testing; model development; molecular modeling; novel strategies; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Albert Cunningham, PI This project will use structure-activity relationship (SAR) modeling to define groups of tissue-specific carcinogens followed by comparative toxicogenomics and proteome analyses to identify the molecular targets they interact with or influence. This subproject has three specific aims: 1. Model Development: Update existing SAR models for rodent carcinogenicity that will serve as "control" models and a set of "experimental" SAR models based on target tissue-specific chemical carcinogenesis. The control models will be based on the traditional SAR approach of contrasting carcinogens to noncarcinogens and the experimental models will be based on a new approach of contrasting chemical carcinogens from one site to those of all other sites. In essence, the control models will handle the question of "What makes a chemical a carcinogen?" and the experimental models will tackle the problem of "What makes a carcinogen target a specific tissue?" This aim will use the Core C facility (Molecular Modeling) to carry out this approach. 2. Toxicophore Identification: Based on information developed in Aim 1, we will identify toxicophore-defined sets of compounds (i.e., with similar structure and biological activity) associated with tissue-specific carcinogenesis. Then we will refine toxicophores from these models with ligand-based 3D SAR methods and develop small libraries of suitable compounds for in vitro testing. This aim will use Core C (Molecular Modeling). 3. Genome/Proteome Target Identification: Using the compounds from the toxicophore libraries developed in Aim 2 as chemical probes, we will assay site-matched cell lines in order to identify the molecular targets with which they interact. Comparative toxicogenomics and proteomics will be used to identify the specific molecular targets associated with tissue-specific carcinogenicity. This aim will use Cores B (Microarray facility).

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 阿尔伯特·坎宁安，PI 该项目将使用构效关系（SAR）模型来定义组织特异性致癌物组，然后进行比较毒物基因组学和蛋白质组分析，以确定它们相互作用或影响的分子靶标。 该子项目有三个具体目标： 1.模型开发：更新现有的啮齿动物致癌性SAR模型，作为“控制”模型和一套基于目标组织特异性化学致癌作用的“实验”SAR模型。控制模型将基于对比致癌物与非致癌物的传统SAR方法，而实验模型将基于对比一个地点与所有其他地点的化学致癌物的新方法。本质上，控制模型将解决“什么使化学物质成为致癌物？”的问题。实验模型将解决“什么使致癌物针对特定组织？”的问题。该目标将使用核心 C 设施（分子建模）来执行该方法。 2. 毒物识别：根据目标 1 中开发的信息，我们将识别与组织特异性癌发生相关的毒物定义的化合物组（即具有相似的结构和生物活性）。然后，我们将使用基于配体的 3D SAR 方法从这些模型中提炼毒物载体，并开发适合体外测试的小型化合物库。该目标将使用 Core C（分子建模）。 3. 基因组/蛋白质组目标识别：使用目标 2 中开发的毒载体库中的化合物作为化学探针，我们将分析位点匹配的细胞系，以识别与其相互作用的分子目标。比较毒物基因组学和蛋白质组学将用于识别与组织特异性致癌性相关的特定分子靶标。该目标将使用 Cores B（微阵列设施）。