Pharmacogenomics of Membrane Transporters

膜转运蛋白的药物基因组学

• 批准号: 8312768
• 负责人: KATHLEEN M GIACOMINI
• 金额: $ 51.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8312768
• 关键词: Academia; Adverse reactions; African American; Antidiabetic Drugs; Back; Bioinformatics; Biological; Biometry; Blood; CCL21 gene; Cells; Chromosome Mapping; Clinical; Clinical Research; Computing Methodologies; Custom; DNA; DNA Resequencing; Data; Databases; Deposition; Drug usage; Genes; Genomics; Genotype; Goals; Grant; Health; Human; Human Genetics; Individual; Industry; Interdisciplinary Study; Kidney; Knowledge; Laboratories; Liver; Maps; Mediating; Membrane Transport Proteins; Metformin; Methodology; Methods; Mus; Nucleic Acid Regulatory Sequences; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Phenotype; Play; Population; RNA; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Resources; Role; Sampling; Staging; Testing; Therapeutic; Tissue Sample; Tissues; Toxic effect; Variant; cohort; design; experience; follow-up; functional genomics; genetic variant; genome wide association study; genome-wide; healthy volunteer; innovation; mouse model; next generation; novel; predictive modeling; repository; research study; response; tool; web site

DESCRIPTION (provided by applicant): Membrane transporters in the SLC and ABC superfamilies are of enormous pharmacological importance, serving as critical determinants of drug disposition and response. Building on the extensive infrastructure established during the previous granting cycles, the proposed research will focus on transporters in the liver and kidney, which interact with virtually all known drugs in mediating drug disposition, response and toxicity. Through computationally driven functional studies and multiple clinical studies, the proposed research will test the hypothesis that genetic variants in membrane transporters contribute to variation in drug response. The functional genomic studies will have a major emphasis on variants in noncoding regions, expanding on our current efforts, which are focused largely on nonsynonymous variants. For these studies, we propose to: (a) functionally characterize variants within regulatory regions of transporter genes; (b) associate sequence variants with transporter expression levels in liver and kidney samples; and (c) develop predictive models for substrate-dependent effects of nonsynonymous variants. In addition to common variants, we will continue to study rare variants as our previous studies have demonstrated their functional importance. Three types of clinical studies will be performed: (a) genotype-driven hypothesis testing studies in SOPHIE, a unique cohort of healthy volunteers who have provided DNA and agreed to be called back for follow-up studies; (b) a large genomewide association study in African Americans of response to the anti-diabetic drug, metformin, a drug that interacts with multiple transporters; and (c) collaborative studies on clinical samples in which a custom-designed transporter-ADME SNP chip will be used to identify genetic variants in transporters that are determinants of toxicities and response to multiple drugs. Our project has recruited a world-class multidisciplinary research team with computational, experimental and clinical expertise, who will apply innovative methodologies including RNA-seq, Next-generation sequencing and multi-stage genomewide association analysis. Three research cores, bioinformatics, biostatistics and genomics, will provide support for these highly mechanistic and clinically important studies.

描述（由申请方提供）：SLC和ABC超家族中的膜转运蛋白具有巨大的药理学重要性，是药物处置和反应的关键决定因素。在前几个资助周期建立的广泛基础设施的基础上，拟议的研究将侧重于肝脏和肾脏中的转运蛋白，这些转运蛋白与几乎所有已知的药物相互作用，介导药物处置，反应和毒性。通过计算驱动的功能研究和多项临床研究，拟议的研究将测试膜转运蛋白的遗传变异有助于药物反应变化的假设。功能基因组学研究将主要侧重于非编码区的变异，扩大我们目前的努力，主要集中在非同义变异。对于这些研究，我们建议：（a）功能特性的转运蛋白基因的调控区域内的变体;（B）关联的序列变异与转运蛋白在肝脏和肾脏样本的表达水平;（c）开发预测模型的非同义变异的底物依赖性的影响。除了常见的变异，我们将继续研究罕见的变异，因为我们以前的研究已经证明了它们的功能重要性。将进行三种类型的临床研究：（a）在SOPHIE中进行基因型驱动的假设检验研究，SOPHIE是一个独特的健康志愿者队列，他们提供了DNA并同意被召回进行后续研究;（B）在非裔美国人中进行的大型全基因组关联研究，对抗糖尿病药物二甲双胍的反应，二甲双胍是一种与多种转运蛋白相互作用的药物;以及（c）临床样本的合作研究，其中将使用定制设计的转运蛋白-ADME SNP芯片来鉴定转运蛋白中的遗传变异，这些遗传变异是毒性和对多种药物的反应的决定因素。我们的项目招募了一个拥有计算，实验和临床专业知识的世界级多学科研究团队，他们将应用创新方法，包括RNA-seq，下一代测序和多阶段全基因组关联分析。生物信息学、生物统计学和基因组学这三个研究核心将为这些高度机械性和临床重要性的研究提供支持。