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：
8178832
负责人：
Mary Eileen Dolan
金额：
$ 25.06万
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 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8178832
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. PUBLIC HEALTH RELEVANCE: We are committed to the development of genome-based approaches to prediction of drug response variation among patients. This project will provide results from association studies between drug response and DNA methylation, a crucial mechanism of gene regulation, for a variety of anticancer drugs. This proposed project will allow better characterization of the genetic, epigenetic factors determining complex health-related traits such as drug response and facilitate the realization of personalized medical care.

描述（由申请人提供）：阐明遗传网络的组织并确定它们如何促进细胞和有机物表型在我们的基因组时代仍然是一个巨大的挑战。药物反应和基因表达是由各种遗传和非遗传因素控制的复杂表型。开发基于基因组的药物反应预测的方法可能会用于个性化医学中，以最大程度地提高益处并最大程度地减少危害。因此，对确定复杂表型（例如药物反应）的遗传，表观遗传因素的更全面，更好的表征可能会显着使我们的公民的荒地受益，并为我们的生物医学行业提供发展机会。利用在国际HAPMAP项目样本上利用丰富的遗传变异数据（例如，〜310万个单核苷酸多态性，SNP的基因型，SNP），这是人类淋巴母细胞系（LCLS）小组，该小组通过明显健康的个体（通过此提案）进行了co-Piongock of ligongock of llcoggock of llcongock of llcoggock of l contoggog模型，以实现的量子（LCLS），以实验室进行了模型，并实现了LCLONG的模型。这些样品的表型数据。由于基因启动子区域的CpG位点的DNA甲基化是基因表达调节的一种至关重要的机制，从而扩展了当前的整个基因组遗传（例如SNP基因型）和表型数据和表型数据（例如mRNA和MRNA和MicroRNA表达）（在这些样品上），包括这些样品，包括这些样品，包括新的甲基甲基化的甲基甲基化及其在新的甲基化响应中，并在新的甲基化响应中，并构成了新的药物，并构成了一个新的洞察力，并构成了一个新的洞察力，并构成了洞察力，并构成了一个新型的洞察力，并构成了洞察力，并构成了综合洞察力，并构成了洞察力的机制。药物基因组和基因表达研究。 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. 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将进行系统地研究，以评估表观遗传学（特定于DNA甲基化）和遗传学（特定于SNP）对12种抗癌药物的细胞毒性的贡献。由于基因表达是整个生物医学研究界的广泛感兴趣，因此，基因表达和药物反应的主要个体级DNA甲基化数据和甲基化相关的特征将在公共领域中作为基于Web的数据库，以易于使用和重新分析。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，我们的调查团队的多学科性质和PI的补充专业知识增强了我们成功地进行该项目的能力。公共卫生相关性：我们致力于开发基于基因组的方法来预测患者药物反应差异。该项目将提供来自药物反应与DNA甲基化之间的关联研究的结果，DNA甲基化是各种抗癌药物的基因调节的关键机制。该提出的项目将允许更好地表征遗传性的，表观遗传因素，这些因素决定了与健康相关的复杂特征，例如药物反应并促进实现个性化医疗护理。