Incorporation of microRNA expression in pharmacogenetic prediction models

将 microRNA 表达纳入药物遗传学预测模型

• 批准号: 7641876
• 负责人: Mary Eileen Dolan
• 金额: $ 20.59万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641876
• 关键词: ABCB1 gene; Adverse event; Adverse reactions; Affect; African; Antimetabolites; Ara-C; Binding; Biological; Biology; Candidate Disease Gene; Carboplatin; Categories; Caucasians; Caucasoid Race; Cell Line; Cells; Cisplatin; Clinical Research; Clinical Trials; Complex; Cytotoxic agent; Drops; Drug Kinetics; Drug toxicity; European; Exhibits; Exons; Figs - dietary; Gene Expression; Gene Expression Profiling; Gene Frequency; Gene Targeting; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Goals; Human; Human Genome; In Vitro; Individual; Individual Differences; International; Laboratories; Left; Linear Regressions; Messenger RNA; Metabolism; Methotrexate; MicroRNAs; Modeling; Molecular Profiling; Nigeria; Normal Cell; Ontology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Phase; Phenotype; Population; Proteins; Regression Analysis; Reporting; Resistance; Risk; Role; Sampling; Single Nucleotide Polymorphism; Site; Testing; Toxic effect; UGT1A1 gene; Underserved Population; Upper arm; Validation; Variant; antitumor agent; base; cancer therapy; capecitabine; cell growth; chemotherapeutic agent; chemotherapy; cytotoxic; cytotoxicity; design; drug efficacy; drug sensitivity; ethnic difference; genetic pedigree; genetic variant; genome wide association study; genome-wide; irinotecan; lymphoblastoid cell line; mRNA Expression; predictive modeling; prevent; protein structure; public health relevance; research clinical testing; response; trait; tumor; yellow-1

DESCRIPTION (provided by applicant): Most chemotherapeutic drugs affect both tumor and normal cells, are ineffective in a number of patients, and exhibit serious toxicity; hence developing predictive models that identify patients at risk for adverse reactions and/or non-response to chemotherapeutic agents prior to treatment is essential. An objective of this proposal is to take a concerted translational effort to elucidate the underlying cause for the inter-ethnic differences in sensitivity to chemotherapy. In this proposal, we will focus on two classes of cytotoxic agents: platinating agents (cisplatin and carboplatin) and antimetabolites (capecitabine and Ara-C), of which significant inter-ethnic differences in cellular sensitivity have been observed in vitro. Our hypothesis is that there are microRNA (miRNA) expression differences in individuals of African descent compared to individuals of European descent that contribute, at least in part, to the difference in sensitivity to chemotherapy-induced cytotoxicity in these two populations. Our long-term goal is to develop an unbiased genome-wide model to identify germline genetic variants, mRNA or miRNA expression including those in an underserved population, that predict risk for adverse reactions and non-response to chemotherapy. Our hypothesis is that there is a set of germline pharmacogenetic polymorphisms associated with the expression of miRNA that affect chemotherapy-induced cytotoxicity and these polymorphisms exhibit interethnic differences. Our specific aims are 1) To quantify genome-wide miRNA expression in HapMap lymphoblastoid cell lines (LCLs) and to identify SNPs associated with miRNA expression and chemotherapy-induced cytotoxicity; 2) To identify mRNA and miRNA expression signatures that significantly correlate with chemotherapy sensitivity and to compare the miRNA expression chemotherapeutic sensitivity signatures in different ethnic populations; 3) To replicate our findings in additional LCLs. PUBLIC HEALTH RELEVANCE: This proposal is intended to better understand how genetic variation contributes to individual sensitivity to chemotherapy. The long term goal is to identify patients, using their genetic make up, that are at risk for toxicities associated with chemotherapy with the intent to reduce their chances of an adverse event.

描述（由申请人提供）：大多数化疗药物影响肿瘤和正常细胞，在许多患者中无效，并表现出严重的毒性;因此，开发预测模型，在治疗前识别具有不良反应和/或对化疗药物无反应风险的患者是至关重要的。本提案的目的是采取协调一致的翻译努力，阐明种族间化疗敏感性差异的根本原因。在本提案中，我们将重点关注两类细胞毒性药物：铂类药物（顺铂和卡铂）和抗代谢药物（卡培他滨和阿糖胞苷），其中已在体外观察到细胞敏感性的显著种族间差异。我们的假设是，非洲裔个体与欧洲裔个体相比，存在微小RNA（miRNA）表达差异，这至少部分导致了这两个人群对化疗诱导的细胞毒性的敏感性差异。我们的长期目标是开发一个无偏见的全基因组模型，以识别生殖系遗传变异，mRNA或miRNA表达，包括那些在服务不足的人群中，预测不良反应和化疗无反应的风险。我们的假设是，存在一组与影响化疗诱导的细胞毒性的miRNA表达相关的生殖系药物遗传学多态性，并且这些多态性表现出种族间差异。我们的具体目标是：1）定量HapMap淋巴母细胞样细胞系（LCL）中全基因组miRNA的表达，并鉴定与miRNA表达和化疗诱导的细胞毒性相关的SNP; 2）鉴定与化疗敏感性显著相关的mRNA和miRNA表达特征，并比较不同种族人群中miRNA表达化疗敏感性特征; 3）在其他LCL中复制我们的发现。公共卫生相关性：该提案旨在更好地了解遗传变异如何影响个体对化疗的敏感性。长期目标是利用患者的遗传组成来识别具有与化疗相关的毒性风险的患者，以降低其发生不良事件的机会。