Association and Function of Opioid Receptor Gene Variants to Substance Dependence

阿片受体基因变异与物质依赖性的关联和功能

• 批准号: 7320738
• 负责人: Huiping Zhang
• 金额: $ 8.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320738
• 关键词: Adverse effects; Affect; Affinity; African American; Alcohol dependence; Alcohols; Alleles; American; Appendix; Binding; Binding Sites; Biological Assay; Buprenorphine; Clinical; Clinical Trials; Code; Complex; DNA Sequence; Diagnosis; Disease; Early Diagnosis; Early Intervention; Economics; Effectiveness; Electrophoretic Mobility Shift Assay; Environmental Risk Factor; Ethnic group; European; Family; Functional RNA; Future; Gene Expression; Genes; Genetic; Genetic Models; Genetic Variation; Genotype; Goals; Haplotypes; Human; Individual; Lead; Luciferases; Mediating; Mentors; Messenger RNA; Minor; Naloxone; Opiate Addiction; Opioid; Opioid Receptor; Outcome; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Phenotype; Polymerase Chain Reaction; Population; Proteins; Range; Receptor Gene; Recruitment Activity; Reporter Genes; Research Personnel; Research Training; Rewards; Risk; Safety; Single Nucleotide Polymorphism; Structure; Substance Addiction; Testing; Time; Training; Treatment outcome; Variant; Western Blotting; Withdrawal; Work; base; case control; dosage; experience; genetic association; improved; interest; neuropsychiatry; non-opioid analgesic; programs; psychosocial; racial difference; receptor; receptor binding; response; transcription factor

DESCRIPTION (provided by applicant): This K99/ROO application seeks support for additional research training which will enable the applicant to become an independent investigator in neuropsychiatric genetics. The training goal will be achieved through a project aimed to identify substance (drug and/or alcohol) dependence (SD)-associated variants in three opioid receptor genes (OPRM1, OPRD1 and OPRK1) and interpret the mechanism of the association. In the mentored phase (year 2007-2009), I will use population- and family-based approaches to study the possible association between opioid receptor gene (OPR) variants and SD in both European Americans (EAs) and African Americans (AAs). Tightly-spaced single nucleotide polymorphisms (SNPs) spanning OPRs will be genotyped and the association between OPR variants and SD will be analyzed by appropriate statistical programs including structured association analysis. Moreover, gene regions of interest will be screened for new variants, which will be further analyzed for their association with SD. In the independent phase (year 2009-2012), I will focus on functional study of those OPR variants which are found to be associated with SD. For coding region variants, functional study will be conducted by receptor binding assay (to see if OPR variants alter receptor affinity) and Western Blotting (to see if OPR variants modulate receptor protein levels). For non-coding region variants, functional study will be performed by four different approaches: (1) real-time quantitative PCR, which examines whether OPR variants result in increased or decreased gene expression (or mRNA) levels; (2) allelic expression imbalance (AEI) assay, which is an alternative approach to examine whether the two alleles of a variant lead to different expression (or mRNA) levels; (3) Electrophoretic mobility shift assay (EMSA), which examines whether OPR variants are located in transcription factor (TF) binding sites and if they change the binding of a TF to its DNA sequence; (4) luciferase reporter gene assay, which examines whether OPR variants regulate gene expression. These four approaches are complementary. The proposed study will improve our understanding about the influence of OPR variants on SD in EAs and AAs. This work will lay the groundwork for a future R01 project aimed to establish a genetic model for prediction of SD with a set of OPR markers, and to investigate the contribution of OPR variants to the outcome of drug or alcohol dependence treatment or to the racial difference in outcomes of treatment. The applicant is mentored by Dr. Joel Gelernter (primary) and Dr. Jeffrey Gruen (co-mentor), who are both excellent supervisors with substantial experience in genetic studies of complex disorders and who have both mentored numerous previous trainees.