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Expression Genetics in Drug Therapy

药物治疗中的表达遗传学

基本信息

批准号：
8681467
负责人：
WOLFGANG SADEE
金额：
$ 158.77万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-16 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8681467
关键词：
Accounting Address Affect Alleles Amino Acid Sequence Antipsychotic Agents Area Bioinformatics Biological Assay Biological Markers Blood Cells Blood Vessels Brain CETP gene CYP2C9 gene CYP2D6 gene CYP3A4 gene Candidate Disease Gene Cardiovascular Diseases Cardiovascular system Central Nervous System Diseases Child Clinic Clinical Clinical Research Clinical Trials Clinical assessments Complement Complex Coronary Arteriosclerosis Coronary heart disease DNA DRD1 gene DRD2 gene Data Databases Dexamethasone Disease Disease Outcome Dopamine Dose Drug Kinetics Drug Receptors Drug Targeting ESR1 gene Early Intervention Elements Environment Enzymes Epigenetic Process Estrogen Receptors Failure Female Future Gene Expression Profiling Gene Expression Regulation Gene Targeting Genes Genetic Genetic Markers Genetic Polymorphism Genetic Transcription Genomics Genotype Glucocorticoid Receptor Glucocorticoids Goals Heart Heat-Shock Proteins 90 High Density Lipoproteins Human Individual Kidney Knowledge Laboratories Lead Link Liver Low-Density Lipoproteins Measures Messenger RNA Methods MicroRNAs Molecular Molecular Genetics Mutation Myocardial Infarction NR3C1 gene Nephrotic Syndrome Outcome Oxidoreductase Pathway interactions Patients Pattern Penetrance Peptide Sequence Determination Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Pharmacotherapy Phase Play Prevention Primer Extension Process Proteins Psychotic Disorders RNA Splicing Receptor Signaling Regulation Reporter Genes Research Resistance Resources Role Scanning Schizophrenia Science Scientist Series Signal Pathway Signal Transduction Site Source Specificity Steroid Receptors Steroids Surveys TDO2 gene Testing Therapeutic Tissues Toxic effect Transcript Translating Translation Process Treatment outcome Variant Women&apos s Health base candidate identification clinical phenotype cohort disease registry dosage drug metabolism expectation experience first episode psychosis fitness functional genomics gene interaction genetic analysis genetic selection genetic variant genome wide association study genome-wide analysis improved in vivo innovation insight lipid metabolism mRNA Expression next generation programs promoter prospective protein expression receptor repository research clinical testing response statistics transcription factor treatment response

项目摘要

Understanding the genetic basis of disease and drug response has the potential to improve therapy and enable early intervention or prevention. However, the main genetic factors remain only partially understood, even while the number of candidate genes is rapidly growing, as a result of genome-wide association studies. Polymorphisms that alter protein sequence are readily detectable, but growing evidence indicates that regulatory polymorphisms are more prevalent, affecting mRNA expression, processing, and translation. Yet, regulatory variants are difficult to detect, and moreover, their functions depend on tissue context and environment, so that a majority remains hidden. The central goal of this proposal is a comprehensive discovery of regulatory polymorphisms in ~200 pharmacotherapeutic candidate genes, followed by molecular studies to understand the underlying mechanisms, and clinical evaluation in drug therapy - the first such systematic study in pharmacogenomics. We have developed a comprehensive approach to the discovery of regulatory polymorphisms, measuring allelic mRNA expression, processing, and translation in relevant human target tissues. This approach has already revealed unexpected and frequent regulatory variants in genes encoding drug metabolizing enzymes and receptors, gaining a powerful link between genotype of proven function and clinical outcomes (examples: DRD2, TPH2, ACE, VKORC1, CETP, and CYP3A4). These results support a critical role for regulatory polymorphisms in drug response. The main focus in this proposal is on drug metabolism genes and impact on pharmacokinetics-pharmacodynamics. In addition, building on other ongoing studies, the project includes genes encoding drug receptors/targets, with focus on CNS disorders (schizophrenia) and cardiovascular diseases (myocardial infarction, lipid metabolism), to be tested in association studies led by experienced clinical scientists. Driven by the motto 'from clinic to laboratory', new genetic studies have been initiated on estrogen and glucocorticoid receptors, the latter to be tested in glucocorticoid-resistant nephrotic syndrome in children. The long-term goal is to develop and validate genetic biomarker panels for optimizing personalized drug therapy.

了解疾病和药物反应的遗传基础有可能改善治疗并使早期干预或预防成为可能。然而，主要的遗传因素仍然只被部分理解，即使候选基因的数量正在迅速增长，作为全基因组关联研究的结果。改变蛋白质序列的多态性很容易检测到，但越来越多的证据表明，调控多态性更为普遍，影响mRNA的表达、加工和翻译。然而，调控变异很难被检测到，而且它们的功能依赖于组织背景和环境，因此大多数调控变异仍然是隐藏的。该提案的中心目标是全面发现约200个药物治疗候选基因的调控多态性，随后进行分子研究以了解其潜在机制，并在药物治疗中进行临床评估-这是药物基因组学中首次进行此类系统研究。我们开发了一种全面的方法来发现调控多态性，测量等位基因mRNA在相关人类靶组织中的表达、加工和翻译。这种方法已经揭示了编码药物代谢酶和受体的基因中意想不到的和频繁的调节变异，在已证实功能的基因型和临床结果之间获得了强有力的联系（例如：DRD2， TPH2， ACE, VKORC1， CETP和CYP3A4）。这些结果支持了调控多态性在药物反应中的关键作用。本提案的重点是药物代谢基因及其对药代动力学的影响。此外，在其他正在进行的研究的基础上，该项目包括编码药物受体/靶点的基因，重点是中枢神经系统疾病（精神分裂症）和心血管疾病（心肌梗死、脂质代谢），将在经验丰富的临床科学家领导的关联研究中进行测试。在“从临床到实验室”的座右铭的推动下，已经开始了关于雌激素和糖皮质激素受体的新的遗传研究，后者将在儿童糖皮质激素抵抗性肾病综合征中进行测试。长期目标是开发和验证遗传生物标志物面板，以优化个性化药物治疗。

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Family-based clinical associations and functional characterization of the serotonin 2A receptor gene (HTR2A) in autism spectrum disorder.

自闭症谱系障碍中血清素 2A 受体基因 (HTR2A) 的基于家庭的临床关联和功能特征。

DOI：
10.1002/aur.1383
发表时间：
2014-08
期刊：
AUTISM RESEARCH
影响因子：
4.7
作者：
Smith, Ryan M.;Banks, Wesley;Hansen, Emily;Sadee, Wolfgang;Herman, Gail E.
通讯作者：
Herman, Gail E.

AmpliSeq transcriptome analysis of human alveolar and monocyte-derived macrophages over time in response to Mycobacterium tuberculosis infection.

DOI：
10.1371/journal.pone.0198221
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Papp AC;Azad AK;Pietrzak M;Williams A;Handelman SK;Igo RP Jr;Stein CM;Hartmann K;Schlesinger LS;Sadee W
通讯作者：
Sadee W

Allele-Selective Transcriptome Recruitment to Polysomes Primed for Translation: Protein-Coding and Noncoding RNAs, and RNA Isoforms.

DOI：
10.1371/journal.pone.0136798
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Mascarenhas R;Pietrzak M;Smith RM;Webb A;Wang D;Papp AC;Pinsonneault JK;Seweryn M;Rempala G;Sadee W
通讯作者：
Sadee W

Design and implementation of a randomized controlled trial of genomic counseling for patients with chronic disease.

DOI：
10.3390/jpm4010001
发表时间：
2014-01-08
期刊：
Journal of personalized medicine
影响因子：
0
作者：
Sweet K;Gordon ES;Sturm AC;Schmidlen TJ;Manickam K;Toland AE;Keller MA;Stack CB;García-España JF;Bellafante M;Tayal N;Embi P;Binkley P;Hershberger RE;Sadee W;Christman M;Marsh C
通讯作者：
Marsh C

DFI: gene feature discovery in RNA-seq experiments from multiple sources.

DFI：RNA-seq 实验中多个来源的基因特征发现。