Pharmacogenomics of a Cytidine Analogue, Gemcitabine

胞苷类似物吉西他滨的药物基因组学

• 批准号: 7525350
• 负责人: Liewei Wang
• 金额: $ 16.29万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7525350
• 关键词: 6-Mercaptopurine; Affect; Alternative Splicing; Antimetabolites; Antineoplastic Agents; Antineoplastic Antimetabolites; Back; Biological Assay; Biological Models; CYP2D6 gene; Cancer Patient; Cancer cell line; Candidate Disease Gene; Cell Line; Cells; Classification; Clinic; Clinical; Code; Complement; Comprehensive Cancer Center; Count; Cytidine; DNA; DNA Resequencing; Data; Deoxycytidine; Depth; Development; Discipline; Disease; Doctor of Philosophy; Drug Delivery Systems; Drug Transport; Drug toxicity; Electrophoresis; Electrophoretic Mobility Shift Assay; End Point; Environment; Enzymes; Ethnic group; Exons; Experimental Designs; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Grant; Haplotypes; Hearing; High Pressure Liquid Chromatography; Human; Human Herpesvirus 4; Individual; Institutes; Introns; Laboratories; Lead; Life Expectancy; Linkage Disequilibrium; Malignant neoplasm of pancreas; Mammalian Cell; Maps; Mentors; Messenger RNA; Metabolic Activation; Metabolism; Non-Small-Cell Lung Carcinoma; Nucleic Acid Regulatory Sequences; Numbers; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phenotype; Platelet Count measurement; Play; Principal Investigator; Prodrugs; Promoter Regions; Protein Overexpression; Proteins; Purines; Pyrimidine; Pyrimidines; RNA Splicing; Reporter Genes; Reproduction spores; Research; Research Design; Research Personnel; Research Project Grants; Research Training; Resistance; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Sampling Studies; Series; Small Interfering RNA; Solid Neoplasm; TPMT gene; Techniques; Testing; Time; Tissue Sample; Toxic effect; Training; Transition Career Development Award (K22); Translating; Translational Research; Tumor Cell Line; Tumor Tissue; UDP-Glucuronosyltransferase 1A1; UGT1A1 gene; United States National Institutes of Health; Untranslated Regions; Variant; analog; anticancer research; base; cancer therapy; career; cell transformation; cytotoxicity; design; drug efficacy; drug metabolism; enzyme activity; gemcitabine; genetic analysis; genome wide association study; indium arsenide; inorganic phosphate; insight; interest; irinotecan; knock-down; lymphoblastoid cell line; mRNA Expression; mRNA Stability; neutrophil; novel; programs; promoter; protein function; purine; research study; response; thiopurine; time use; tool; trait; transcription factor; tumor

DESCRIPTION (provided by applicant): This proposal represents an application for an NCI Transition Career Development Award (K22) on behalf of Liewei Wang, M.D.-Ph.D. Dr. Wang has laboratory-based Cancer Research training in pharmacogenomics -- with an emphasis on the pharmacogenomics of purine antimetabolites such as 6-mercaptopurine. The applicant initiated her independent research career approximately a year ago, and this proposal builds on her training in Cancer Research to focus on pharmacogenomic studies of the pyrimidine antineoplastic antimetabolite, gemcitabine. The proposed studies will take advantage of the outstanding environment at the Mayo Clinic and a series of NIH-Mayo initiatives, including the NIH Comprehensive Cancer Center, the NIH Pharmacogenetics Research Network (PGRN) grant and the NIH Pancreatic Cancer SPORE. The applicant proposes to utilize a "Human Variation Panel" cell line model system that expresses virtually all of the genes encoding proteins that participate in "the gemcitabine pathway", i.e., drug transport, metabolism, activation and targets. This Human Variation Panel consists of 203 cell lines obtained from three different ethnic groups. The applicant has obtained in-depth resequencing data for these genes in all 203 cell lines, as well as basal gene expression array data and genome-wide SNP data. She has also generated gemcitabine cytotoxicity data for the cell lines that will make it possible to perform both gemcitabine pathway-based and genome-wide SNP pharmacogenomic genotype-phenotype association analyses. Hypotheses generated with this model system will then be tested using DNA samples from patients with pancreatic cancer who were treated with gemcitabine, and candidate genes/SNPs identified with the cell lines and/or patient samples will be characterized functionally in the laboratory. These studies will not only utilize modern statistical genetic and high throughput genomic techniques to test the hypothesis that genetic variation in germline DNA might contribute to gemcitabine sensitivity and/or resistance, but will also serve to build on the applicant's training in Cancer Research to make it possible for her to gain additional training in statistical genetics with Dr. Daniel Schaid as her Mentor. Therefore, the proposed studies will provide an ideal "Transition Career Development" path to extend her pharmacogenomic studies of antineoplastic drugs and to make it possible for her to submit a future R01 Cancer Research grant.

描述（由申请人提供）：本提案代表王列伟医学博士-博士申请 NCI 过渡职业发展奖 (K22)。 Wang 博士接受过基于实验室的药物基因组学癌症研究培训，重点是 6-巯基嘌呤等嘌呤抗代谢物的药物基因组学。申请人大约一年前开始了她的独立研究生涯，该提案建立在她在癌症研究方面的培训基础上，重点关注嘧啶抗肿瘤抗代谢物吉西他滨的药物基因组学研究。拟议的研究将利用梅奥诊所的优越环境和一系列 NIH-梅奥倡议，包括 NIH 综合癌症中心、NIH 药物遗传学研究网络 (PGRN) 拨款和 NIH 胰腺癌 SPORE。申请人提议利用“人类变异面板”细胞系模型系统，该系统表达几乎所有编码参与“吉西他滨途径”（即药物转运、代谢、激活和靶标）的蛋白质的基因。该人类变异面板由来自三个不同种族的 203 个细胞系组成。申请人获得了所有203个细胞系中这些基因的深度重测序数据，以及基础基因表达阵列数据和全基因组SNP数据。她还生成了细胞系的吉西他滨细胞毒性数据，这使得进行基于吉西他滨途径和全基因组 SNP 药物基因组基因型-表型关联分析成为可能。然后，将使用来自接受吉西他滨治疗的胰腺癌患者的 DNA 样本来测试用该模型系统生成的假设，并且用细胞系和/或患者样本鉴定的候选基因/SNP 将在实验室中进行功能表征。这些研究不仅将利用现代统计遗传学和高通量基因组技术来检验种系 DNA 中的遗传变异可能导致吉西他滨敏感性和/或耐药性的假设，而且还将有助于申请人在癌症研究方面的培训，使她有可能在 Daniel Schaid 博士作为她的导师的情况下获得统计遗传学方面的额外培训。因此，拟议的研究将提供一条理想的“过渡职业发展”路径，以扩展她抗肿瘤药物的药物基因组学研究，并使她有可能提交未来的 R01 癌症研究资助。