Pharmacogenomics of Membrane Transporters

膜转运蛋白的药物基因组学

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：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。基于之前的授权周期中建立的广泛基础设施，拟议的研究将重点关注肝脏和肾脏中的转运蛋白，它们与几乎所有已知药物相互作用，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，拟议的研究将检验膜转运蛋白的遗传变异导致药物反应变化的假设。功能基因组研究将重点关注非编码区域的变异，扩展我们目前主要关注非同义变异的努力。对于这些研究，我们建议：（a）功能性地表征转运蛋白基因调控区域内的变异； (b) 将序列变异与肝脏和肾脏样本中的转运蛋白表达水平相关联； (c) 开发非同义变异的底物依赖性效应的预测模型。除了常见变异之外，我们还将继续研究罕见变异，因为我们之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 是一组独特的健康志愿者，他们提供了 DNA 并同意被召回进行后续研究； (b) 一项针对非裔美国人的大型全基因组关联研究，研究对象是抗糖尿病药物二甲双胍（一种与多种转运蛋白相互作用的药物）的反应； (c) 对临床样本进行合作研究，其中将使用定制设计的转运蛋白-ADME SNP 芯片来识别转运蛋白中的遗传变异，这些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支具有计算、实验和临床专业知识的世界一流的多学科研究团队，他们将应用包括RNA-seq、下一代测序和多阶段全基因组关联分析在内的创新方法。生物信息学、生物统计学和基因组学三个研究核心将为这些高度机械化和临床重要的研究提供支持。