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: 7813372
• 负责人: Huiping Zhang
• 金额: $ 24.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813372
• 关键词: Address; Adverse effects; Affect; African American; Age; Alcohols; Alleles; American; Applications Grants; Biological; Biological Assay; Buprenorphine; Child Abuse; Cocaine; Connecticut; Consumption; DNA; DNA Methylation; DNA Resequencing; DNA Sequence; Data; Diagnosis; Disease; Drug Addiction; Early Diagnosis; Effectiveness; Epigenetic Process; European; Event; Future; Genes; Genetic Research; Genetic Variation; Genome; Genotype; Haplotypes; Healthcare Systems; Heroin; Individual; Intervention; Kindling (Neurology); Laboratories; Left; Life; Linkage Disequilibrium; Mediating; Mentors; Methods; Modification; Morphine; Naloxone; Nucleic Acid Regulatory Sequences; Opiate Addiction; Opioid; Opioid Peptide; Opioid Receptor; Outcome; POMC gene; Patients; Peptide Receptor; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Phenotype; Polymerase Chain Reaction; Prevention strategy; Pro-Opiomelanocortin; Psychiatry; Receptor Gene; Reporter Genes; Rewards; Risk; Safety; Substance Addiction; System; Techniques; Technology; Testing; Time; Trauma; Treatment outcome; Variant; Western Blotting; Work; case control; depression; design; dosage; effective therapy; falls; gel mobility shift assay; genetic variant; improved; next generation; prodynorphin; proenkephalin; receptor binding; response; treatment response

Tfiis is a K99 to ROO transition application which seeks further support for studying the association of four opioid receptor genes (0PRM1, 0PRD1, 0PRK1, and 0PRL1) and four opioid peptide genes (POMC, PDYN, PENK, and PNOC) genes and substance dependence (SD) in African Americans (AAs) and European Americans (EAs). In the K99 phase, we identified several opold receptor and peptide gene variants which were significantly associated with SD. However, since only a limited number of variants were selected and tested for their association with SD, the causal variant might have been ignored. In addition, it is unknown whether the identified SD-associated variants are functional or they are just in linkage disequilibrium with the causal variant. Therefore, in the ROO phase, we need to further address these Issues. We propose to (1) analyze the association of both common and rare variants with SD by resequencing the opioid receptor and peptide genes in our cases and controls using the next-generation sequencing technique; (2) examine the function of SD-assoclated opioid receptor and peptide gene variants using several approaches including receptor binding assays, Western blotting, real-time quantitative polymerase chain reaction, allelic expression Imbalance assay, electrophoretic mobility gel shift assay, and liclferase reporter gene assay; and (3) Investigate whether DNA metylatlon levels In the regulatory regions ofthe opioid receptor and peptide genes are significantly different between SD affected cases and healthy controls. The proposed study will improve our understanding about the Influence of opioid receptor and peptide gene variants on SD and determine whether epigenetic modification ofthese genes can Increase vulnerability to SD. In addition, it will generate sufficient data for a future ROI project aimed at (1) establishing a set of opiod receptor and peptide gene markers as predictors of SD; and (2) investigating the contribution of variants In these genes to the outcome of SD treatment.

Tfiis是一个K99到ROO的过渡应用程序，它寻求进一步的支持来研究4的关联