Pharmacogenomics of a Cytidine Analogue, Gemcitabine

描述（由申请人提供）：本提案代表王力伟博士申请NCI转型职业发展奖（K22）。Wang博士在药物基因组学方面接受过基于实验室的癌症研究培训，重点是嘌呤抗代谢产物（如6-巯基嘌呤）的药物基因组学。申请人大约在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，专注于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-Mayo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胰腺癌孢子。申请人建议使用“人类变异小组”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”的蛋白质的基因，即药物运输、代谢、激活和靶标。这个人类变异小组由来自三个不同种族的203个细胞系组成。申请人已经获得了所有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。她还为细胞系生成了吉西他滨细胞毒性数据，这将使基于吉西他滨通路和全基因组SNP药物基因组基因型-表型关联分析成为可能。该模型系统产生的假设随后将使用接受吉西他滨治疗的胰腺癌患者的DNA样本进行测试，并在实验室中对细胞系和/或患者样本中鉴定的候选基因/ snp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测试生殖细胞DNA的遗传变异可能有助于吉西他滨敏感性和/或耐药性的假设，而且还将有助于建立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指导下获得统计遗传学方面的额外培训。因此，拟议的研究将为她提供一个理想的“过渡职业发展”路径，以扩展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。

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.