Epigenetic and Genetic Dissection of Drug Response

药物反应的表观遗传学和遗传学剖析

基本信息

批准号：
8309059
负责人：
Mary Eileen Dolan
金额：
$ 21.19万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309059
关键词：
Address Affect Antineoplastic Agents Bioinformatics Biological Assay Biological Models Biomedical Research Busulfan Carboplatin Caring Caucasians Caucasoid Race Cell Line Cell physiology Cells Cisplatin Commit Communities Complex Cyclophosphamide Cytarabine DNA DNA Methylation Data Databases Daunorubicin Development Dissection Drug toxicity Ensure Epigenetic Process Etoposide European Gene Expression Gene Expression Regulation Gene Frequency Gene Targeting Genes Genetic Genetic Determinism Genetic Variation Genome Genomics Genotype Health Human Human Genome Immunoprecipitation Individual Industry International Knowledge Laboratories Maps Measurement Medical Medicine Messenger RNA Methylation MicroRNAs Modeling Nature Online Systems Paclitaxel Patients Pemetrexed Pharmaceutical Preparations Pharmacogenomics Phenotype Phosphoramide Mustard Phosphoramide Mustards Predisposition Promoter Regions Public Domains Publishing Quantitative Trait Loci Regulation Research Resources Sampling Single Nucleotide Polymorphism Site Testing Toxic effect Transcript Update Utah Variant base capecitabine cytotoxicity genome wide association study genome-wide hydroxyurea improved insight interest lymphoblastoid cell line mRNA Expression non-genetic novel promoter response success trait

项目摘要

DESCRIPTION (provided by applicant): Elucidating the organization of genetic networks and establishing how they contribute to cellular and organismal phenotypes remain to be a grand challenge in our genomic era. Drug response and gene expression are complex phenotypes that are controlled by various genetic and non-genetic factors. Developing genome-based approaches to prediction of drug response could potentially be used in individualized medicine to maximize benefits and minimize harms. A more comprehensive and better characterization of the genetic, epigenetic factors determining complex phenotypes such as drug response, therefore, may significantly benefit the heath of our citizens and provide development opportunities for our biomedical industry. Taking advantage of the rich genetic variation data (e.g., genotypes of ~3.1 million single nucleotide polymorphisms, SNPs) on the International HapMap Project samples, a panel of human lymphoblastoid cell lines (LCLs) derived from apparently healthy individuals, the Dolan (Co-PI of this proposal) Laboratory has pioneered using the LCL model system in pharmacogenomic discovery by integrating genetic and phenotypic data on these samples. Since DNA methylation at the CpG sites of gene promoter regions is a crucial mechanism of gene expression regulation, expanding the current whole genome genetic (e.g., SNP genotypes) and phenotypic data (e.g., mRNA and microRNA expression) on these samples to include DNA methylation may provide novel and critical insights into the underlying mechanism of individual drug response and expression regulation, and reflect a significantly new direction for pharmacogenomic and gene expression studies. We therefore propose to use the NimbleGen 2.1M Deluxe Promoter Array and the MeDIP (methylated DNA immunoprecipitation) assay to profile the natural variation in DNA methylation status at all known promoter regions in 60 unrelated cell lines from the HapMap CEU (derived from Caucasian residents from Utah, USA) samples of Northern and Western European ancestry. The relationships across SNP genotypes, promoter DNA methylation status, gene expression and drug response will be investigated systematically to evaluate the contribution of epigenetics (specifically, DNA methylation) and genetics (specifically, SNPs) to the cytotoxicities of 12 anticancer drugs. Since gene expression is of broad interest to the entire biomedical research community, the primary individual-level DNA methylation data and the methylation-associated signatures for both gene expression and drug response will be put in public domain as a web-based database for easy use and re-analysis. Upon completion, this exploratory project will significantly enhance scientific knowledge in the broad fields of genomics and pharmacogenomics. Finally, the multi-disciplinary nature of our investigative team and the complementary expertise of PIs enhance our ability to conduct the proposed project successfully.

描述（由申请人提供）：阐明遗传网络的组织并确定它们如何对细胞和有机体表型做出贡献仍然是我们基因组时代的一项巨大挑战。药物反应和基因表达是复杂的表型，受各种遗传和非遗传因素控制。开发基于基因组的方法来预测药物反应可能会用于个体化医疗，以最大限度地提高效益并最大限度地减少危害。因此，对决定药物反应等复杂表型的遗传、表观遗传因素进行更全面、更好的表征，可能会极大地有益于我们公民的健康，并为我们的生物医药行业提供发展机会。利用国际 HapMap 项目样本中丰富的遗传变异数据（例如，约 310 万个单核苷酸多态性 (SNP) 的基因型），一组源自表面健康个体的人类淋巴母细胞系 (LCL)，Dolan (Co-该提案的 PI）实验室通过整合这些样本的遗传和表型数据，率先在药物基因组学发现中使用 LCL 模型系统。由于基因启动子区域 CpG 位点的 DNA 甲基化是基因表达调控的重要机制，因此扩展这些样本上当前的全基因组遗传（例如，SNP 基因型）和表型数据（例如，mRNA 和 microRNA 表达）以包括 DNA 甲基化可能为个体药物反应和表达调控的潜在机制提供新颖和批判性的见解，并反映药物基因组学和基因表达研究的一个重要的新方向。因此，我们建议使用 NimbleGen 2.1M Deluxe 启动子阵列和 MeDIP（甲基化 DNA 免疫沉淀）测定来分析来自 HapMap CEU（源自白种人居民）的 60 个不相关细胞系中所有已知启动子区域 DNA 甲基化状态的自然变异。美国犹他州）北欧和西欧血统的样本。将系统地研究 SNP 基因型、启动子 DNA 甲基化状态、基因表达和药物反应之间的关系，以评估表观遗传学（特别是 DNA 甲基化）和遗传学（特别是 SNP）对 12 种抗癌药物细胞毒性的贡献。由于基因表达受到整个生物医学研究界的广泛关注，因此主要的个体水平 DNA 甲基化数据以及基因表达和药物反应的甲基化相关特征将作为基于网络的数据库置于公共领域，以便于使用并重新分析。完成后，该探索性项目将显着增强基因组学和药物基因组学广泛领域的科学知识。最后，我们调查团队的多学科性质和 PI 的互补专业知识增强了我们成功开展拟议项目的能力。