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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 艾伯特·坎宁安，派 该项目将使用结构-活性关系(SAR)模型来确定组织特定致癌物的组，然后进行比较毒理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。 这一分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的合成孔径雷达模型，作为“对照”模型，以及一套基于靶组织特定化学致癌作用的“实验性”合成孔径雷达模型。控制模型将基于对比致癌物和非致癌物的传统SAR方法，而实验模型将基于将一个地点的化学致癌物与所有其他地点的化学致癌物进行对比的新方法。从本质上讲，控制模型将处理“是什么让一种化学物质成为致癌物质？”实验模型将解决“是什么让致癌物以特定组织为靶标？”这一目标将使用核心C设施(分子建模)来实现这一方法。 2.毒物识别：根据目标1中发展的信息，我们将识别与特定组织致癌有关的毒物定义的化合物集合(即，具有相似的结构和生物活性)。然后，我们将用基于配体的3D SAR方法从这些模型中提炼毒素分子，并开发适合体外测试的小型化合物文库。这一目标将使用核心C(分子建模)。 3.基因组/蛋白质组靶向鉴定：利用AIM 2中开发的毒效团文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，以确定它们相互作用的分子靶点。比较毒理基因组学和蛋白质组学将被用来确定与组织特异性致癌相关的特定分子靶点。这一目标将使用核心B(微阵列设施)。

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).