Gene Expression in Drug-inflammation Models as Predictive of Idiosyncratic ADRS

药物炎症模型中的基因表达作为特殊 ADRS 的预测

• 批准号: 7263212
• 负责人: PATRICIA E GANEY
• 金额: $ 35.79万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263212
• 关键词: Address; Adverse reactions; Animal Model; Animals; Biochemical Markers; Bioinformatics; Biological Assay; Biological Markers; Chemicals; Chlorpromazine; Class; Classification; Clinical Chemistry; Data; Decision Trees; Development; Dose; Drug Design; Drug Industry; Drug Interactions; Drug toxicity; Drug usage; Environmental Risk Factor; Evaluation; Experimental Models; Exposure to; Famotidine; Funding; Gene Expression; Gene Expression Microarray Analysis; Genes; Genetic Predisposition to Disease; Global Change; Goals; Hepatic; Hepatotoxicity; Histamine-2 Receptor Antagonist; Human; Incidence; Individual; Inflammation; Injury; Investments; Lead; Lipopolysaccharides; Liver; Machine Learning; Marketing; Methods; Microarray Analysis; Modeling; Nature; Numbers; Outcome; Pattern; Persons; Pharmaceutical Preparations; Play; Population; Pre-Clinical Model; Preclinical Testing; Predisposition; Public Health; Purpose; Ranitidine; Rattus; Reaction; Reporting; Research; Research Personnel; Role; Safety; Screening procedure; Structure; System; Testing; Time; Tissues; Toxic effect; Training; United States National Institutes of Health; Validation; Withdrawal; animal data; base; data mining; drug development; drug market; health economics; in vitro Model; in vivo; post-market; pre-clinical; predictive modeling; prevent; programs; research study; response; segregation; trovafloxacin

DESCRIPTION (provided by applicant): Idiosyncratic, adverse drug reactions (ADRs) have serious health and economic consequences, yet they are not identified in preclinical testing due to a lack of predictive models. We have developed an animal model that reproduces idiosyncratic liver injury. The model involves treatment of rats with a nontoxic dose of lipopolysaccharide (LPS) to induce mild inflammation followed by treatment with a nontoxic dose of drug. Using this model with two drugs in different pharmacological classes, hepatic gene expression near the onset of injury distinguishes drugs associated with idiosyncratic liver injury in humans from drugs with similar structures that do not have this liability. The long term goal of this research is to evaluate the usefulness of changes in hepatic gene expression in animal models of drug-inflammation interaction as a preclinical predictor of the propensity of drugs to cause idiosyncratic hepatotoxicity in humans. To test the hypothesis that global, hepatic gene expression changes in animal models of inflammation-drug interactions can be used to predict the propensity of drugs to cause human, idiosyncratic liver injury, rats will be cotreated with LPS and one of several drugs (at doses that alone are not hepatotoxic), and microarray analysis of gene expression will be performed on livers. In Specific Aim 1, hepatic gene expression will be analyzed for treatment-related changes. Drugs known to produce idiosyncratic liver injury in people and drugs that are in the same pharmacological classes but are not associated with idiosyncrasy will serve as a "training set" in this Aim. In Aim 2, the microarray data will be analyzed for patterns of expression unique to the drug-inflammation interactions that are associated with idiosyncrasy-producing drugs, and the expression data will be probed for specific genes or sets of genes that determine these unique patterns. In Aim 3, additional drugs will be used as a "validation set" to evaluate the usefulness of the patterns and genes identified in Aims 1 and 2. The immediate product of these studies will be an animal model of drug-inflammation interaction for which a set of genes has been identified that predicts the propensity for a drug to cause idiosyncratic liver injury in people. If successful, these studies will provide models with which to identify preclinically those drugs that could cause this type of liver damage in people. The relevance of this research to public health lies in the potential to prevent the occurrence of "unpredictable", drug-induced liver damage.

描述（由申请人提供）： 特质，不良药物反应（ADR）具有严重的健康和经济后果，但由于缺乏预测模型，它们在临床前测试中未被识别。我们开发了一种复制特质肝损伤的动物模型。该模型涉及用无毒的脂多糖（LP）治疗大鼠，以诱导轻度炎症，然后用无毒的药物治疗。在不同的药理类别中，使用该模型与两种药物，在损伤发作附近的肝基因表达将与人类特质肝损伤相关的药物与具有这种责任的类似结构的药物相关的药物。这项研究的长期目标是评估药物炎症相互作用动物模型中变化的变化的有用性，作为药物倾向引起人类倾向的倾向的临床前预测指标。为了检验全球的假设，可以使用肝脏基因的表达变化在炎症 - 药物相互作用的动物模型中可用于预测药物引起人体，特质肝损伤的倾向，将大鼠与LPS共核，其中一种药物和一种药物之一（单独使用的剂量不是肝毒性毒素），并且是肝毒性毒性分析的，并且将表现出基因表达的表达。在特定的目标1中，将分析肝基因表达，以进行与治疗相关的变化。已知在同一药理学类别中的人和药物中已知的药物损伤，但与特质无关，将作为此目标的“训练集”。在AIM 2中，将分析微阵列数据的表达模式，这些模式与与特质产生的药物相关的药物 - 炎症相互作用所特有的，并将对确定这些独特模式的特定基因或一组基因进行探测表达数据。在AIM 3中，其他药物将用作“验证集”，以评估AIM 1和2中鉴定的模式和基因的实用性。这些研究的直接产物将是一种药物炎症相互作用的动物模型，已确定了一组基因的基因，可预测药物对人造成特征性肝脏损伤的倾向。如果成功，这些研究将提供模型，以鉴定可能导致这种类型的肝脏损害的药物。这项研究与公共卫生的相关性在于有可能防止发生“不可预测”的，药物引起的肝脏损害。