Pharmacogenomics of a Cytidine Analogue, Gemcitabine

胞苷类似物吉西他滨的药物基因组学

基本信息

批准号：
7676128
负责人：
Liewei Wang
金额：
$ 16.45万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/7676128
关键词：
6-Mercaptopurine Animal Model Animals Antibodies Antimetabolites Antineoplastic Agents Antineoplastic Antimetabolites Biological Biological Models Blood Blood Vessels Breast Breast Cancer Cell Cancer cell line Candidate Disease Gene Cell Line Cell Volumes Cells Clinic Collection Comprehensive Cancer Center Computer Simulation Cytidine DNA DNA Resequencing Data Detection Development Diffusion Dimensions Doctor of Philosophy Drug Transport ERBB2 gene Electron Microscopy Environment Ethnic group Filtration Fractionation Frequencies Future Gel Gelatin Gene Expression Generations Genes Genetic Genetic Variation Genomics Genotype Gold Grant Heating Histology Hour Human Image Implant In Vitro Injection of therapeutic agent Laboratories Lasers Lighting Malignant neoplasm of pancreas Mammary Gland Parenchyma Measures Mechanics Membrane Proteins Mentors Metabolism Methods Microscopy Modeling Molecular Sieve Chromatography Mus Normal tissue morphology Optics Pathway interactions Patients Pharmacogenetics Pharmacogenomics Phase Phenotype Physiologic pulse Poloxamer Poloxamers Polyethylene Glycols Polymers Procedures Property Proteins Purines Pyrimidine Pyrimidines Relative (related person)Reproduction spores Research Research Personnel Research Project Grants Research Training Resistance SKBR3 Sampling Series Shapes Signal Transduction Simulate Solutions Suspension substance Suspensions Techniques Testing Theoretical model Tissues Training Transition Career Development Award (K22)Trypan Blue Ultrasonics Ultrasonography United States National Institutes of Health Variant Vascular Endothelial Growth Factors Water Xenograft procedure absorption analog analytical method anticancer research aqueous base career career development cell injury cytotoxicity gemcitabine genome-wide in vivo irradiation malignant breast neoplasm mathematical model mouse model nanoparticle nanorod overexpression particle physical model programs purine research study response surfactant tumor tumor growth two-dimensional vapor vaporization

项目摘要

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）：该提案代表NCI过渡职业发展奖（K22）的申请，代表Liewei Wang，M.D.-Ph.D。 Wang博士接受了基于实验室的药物基因组学癌症研究培训 - 重点是嘌呤抗代谢物（如6-羟基替代谢物）的药物基因组学。申请人大约一年前就开始了她的独立研究生涯，这项提案是基于她在癌症研究中的培训，重点是嘧啶抗塑料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Mayo诊所的杰出环境以及一系列的NIH-Mayo计划，包括NIH综合癌症中心，NIH药物遗传学研究网络（PGRN）Grant和NIH胰腺癌孢子。申请人建议利用“人类变异面板”细胞系模型系统，该模型几乎表达了编码参与“吉西他滨途径”的所有基因，即药物传输，代谢，激活和靶标。该人类变异面板由从三个不同种族获得的203个细胞系组成。申请人在所有203个细胞系中以及基础基因表达阵列数据和全基因组SNP数据中均获得了这些基因的深入重新定制数据。她还为细胞系生成了吉西他滨细胞毒性数据，这将使您可以同时进行基于吉西他滨途径的基于吉西他滨途径和全基因组SNP药物基因组基因型基因型 - 表型缔合分析。然后，将使用该模型系统产生的假设使用胰腺癌患者的DNA样品进行测试，这些患者接受了吉西他滨治疗，并在实验室中功能表征了用细胞系和/或患者样品鉴定的候选基因/SNP。这些研究不仅将利用现代的统计遗传和高通量基因组技术来检验以下假设：种系DNA的遗传变异可能有助于吉西他滨的敏感性和/或抗性，而且还将在申请人的癌症研究中培训，使她有可能与Daniel Schaid Daniel Schaid Schaid are Terors and Mertor进行统计学遗传学有关其他培训。因此，拟议的研究将提供理想的“过渡职业发展”途径，以扩展其对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癌症研究赠款。