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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 Albert Cunningham，PI 该项目将使用结构-活性关系（SAR）建模来定义组织特异性致癌物组，然后进行比较毒理学和蛋白质组学分析，以确定它们相互作用或影响的分子靶点。 该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SAR模型，作为“对照”模型和一组基于靶组织特异性化学致癌作用的“实验”SAR模型。控制模型将基于传统的SAR方法，将致癌物与非致癌物进行对比，而实验模型将基于一种新的方法，将化学致癌物从一个地点与所有其他地点进行对比。从本质上讲，控制模型将处理“是什么使化学物质成为致癌物质？实验模型将解决“是什么使致癌物靶向特定组织？”“这一目标将使用核心C设施（分子建模）来执行这种方法。 2.毒基鉴定：基于目标1中开发的信息，我们将鉴定毒基定义的化合物组（即，具有相似的结构和生物活性）。然后，我们将从这些模型与配体为基础的三维SAR方法和开发合适的化合物在体外测试的小图书馆，完善toxophores。这一目标将使用核心C（分子建模）。 3.基因组/蛋白质组靶标鉴定：使用Aim 2中开发的毒基文库中的化合物作为化学探针，我们将测定位点匹配的细胞系，以鉴定与它们相互作用的分子靶标。比较毒理基因组学和蛋白质组学将用于确定与组织特异性致癌性相关的特定分子靶点。该目的将使用Cores B（微阵列机构）。

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).