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Translatome profiling of nicotine addiction

尼古丁成瘾的翻译组分析

基本信息

批准号：
9550950
负责人：
Jubao Duan
金额：
$ 23.7万
依托单位：
NORTHSHORE UNIVERSITY HEALTHSYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9550950
关键词：
Addictive Behavior Alleles Amygdaloid structure Biological Assay Biological Process Brain Brain region Candidate Disease Gene Cause of Death Chemicals Chronic Disease Data Data Set Development Drug Addiction Electrophysiology (science)Exhibits Expression Profiling Future Gene Expression Gene Targeting Genes Genetic Genetic study Harvest Hippocampus (Brain)Human Hybrids Inbred Strain Intravenous Knowledge Link Maintenance Mass Spectrum Analysis Measures Mediating Messenger RNA Midbrain structure Modeling Molecular Nature Neurobiology Neurons Nicotine Nicotine Dependence Noise Norway Nucleus Accumbens Parents Parkinson Disease Pathologic Pathway interactions Pharmaceutical Preparations Phase Process Property Protein Biosynthesis Proteins Proteomics RNA Rat-1 Rattus Rattus norvegicus Resolution Rewards Ribosomes Risk Factors Rodent Saline Self Administration Sex Characteristics Smoker Smoking Smoking Behavior Surrogate Markers Testing Therapeutic Intervention Tobacco Transcript Translations Treatment Efficacy Variant Ventral Tegmental Area addiction base brain tissue cigarette smoking differential expression dopaminergic neuron genetic variant genome wide association study genome-wide health economics improved induced pluripotent stem cell innovation insight knowledge base neurobiological mechanism neurochemistry nicotine abuse nicotine exposure nicotine use non-smoker novel sex trait transcriptome transcriptome sequencing translatome whole genome

项目摘要

Abstract Smoking is the foremost preventable cause of death. Nicotine (NIC) determines the addictive nature of smoking. In rats, NIC addition has been commonly modeled by intravenous NIC self-administration (SA). We (Dr. Vezina) have recently shown that NIC sensitization, a process that appears after repeated exposure to NIC, can enhance the SA of NIC and other stimulants. NIC sensitization and SA in rats are known to correlate with neurobiological changes in multiple brain regions, however, the molecular basis of the neurobiological changes of NIC sensitization and SA as well as its relevance to human NIC abuse has yet to be determined. We propose to take advantage of the depth and breadth of RNA sequencing (RNAseq) to identify the gene expression profiles of NIC sensitization and SA by quantifying transcripts actively involved in protein synthesis (i.e., translatome) in these processes, and to explore its relevance to enhanced NIC use in humans. Translatome profiling better predicts protein abundance than conventional transcriptome profiling and has higher resolution and dynamic range than mass spectrometry-based proteomic assays. To model NIC sensitization and SA, we will innovatively use F1 progeny of two inbred strains, Fischer-344 (F344) and Brown Norway (BN) since F1 rats are (1) genetically identical, thus minimizing “genetic noise” on measured differential expression and (2) heterozygous at all loci where parental strains have different alleles, thus maximizing the informative heterozygous variants for analyzing allele-specific expression (ASE). We have shown that these F1 rats (F344/BN) exhibit robust NIC sensitization. AIM1: We will characterize the translatome profiles of NIC sensitization and SA by sequencing RNA transcripts bound to ribosomes in ventral tegmental area (VTA) and nucleus accumbens (NAc), the brain regions most relevant to NIC addiction. We will further identify genetic variants showing ASE of sensitization-associated gene translation. AIM2: To examine the relevance of NIC addiction-associated translatome profiles to the enhanced NIC use in humans, we will derive induced pluripotent stem cells (iPSCs) and midbrain DA neurons from both smokers and non-smokers, expose DA neurons to NIC, and examine how the NIC-induced expression changes in iPSC-neurons correlate with those observed in rat brain tissues. For genes correlated with NIC sensitization, we will further evaluate their relevance to human smoking behavior by performing a pathway-based association test in publicly available smoking GWAS datasets. Identifying novel gene targets relevant to NIC sensitization and SA will forge a new path to deepen our understanding of the neurobiology of human NIC abuse, helping develop more effective therapeutic interventions.

摘要