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Role of glial expression in nicotine behaviors for genes identified through human GWAS

通过人类 GWAS 鉴定的基因神经胶质表达在尼古丁行为中的作用

基本信息

批准号：
10701070
负责人：
MARISSA A EHRINGER
金额：
$ 16.97万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10701070
关键词：
Abstinence Acute Address Affect Animal Model Animal Testing Animals Antisense Oligonucleotides Anxiety Astrocytes Behavior Behavior assessment Biochemical Biochemical Markers Biological Biological Assay Body Temperature Brain Brain region Candidate Disease Gene Cell Culture Techniques Chronic Data Development Event Excision Exhibits Family Future Gene Expression Profile Generations Genes Genetic Genetic Transcription Genotype Health Heart Rate Histologic Human Human Genome In Vitro Individual Intake Knockout Mice Knowledge Laboratories Learning Measures Modeling Morphology Motivation Motor Activity Mouse Strains Mus Neurobiology Neurons Nicotine Nicotine Dependence Nicotine Withdrawal Nicotinic Receptors Pathway Analysis Pathway interactions Phase Phenotype Prevention strategy Public Health Publishing RNA Reagent Research Rewards RiboTag Role Sex Differences Signal Transduction Site Sleep Small Interfering RNA Smoking Smoking Behavior Smoking treatment Societies Specificity Substance abuse problem Technology Testing Tobacco Tobacco use Translating United States Variant Vendor Withdrawal Withdrawal Symptom Woman behavioral response brain cell conditional knockout conditioned place preference differential expression drug of abuse druggable target effective therapy electronic cigarette use gene network genome wide association study genome-wide improved in vivo in vivo Model innovation insight interest knock-down mouse model neural nicotine exposure nicotine treatment nicotine use novel response smoking cessation smoking relapse transcriptome transcriptomics

项目摘要

PROJECT SUMMARY Tobacco use rates, including the increasing use of electronic cigarettes, remain at ~20% in the United States, leading to long-term health and financial consequences for individuals, families, and society. Many individuals who desire to quit smoking cannot stop, and the underlying neurobiological effects of smoking on the brain remain poorly understood. Recent large-scale genome-wide association studies (GWAS) have provided convincing evidence for the association of over 2500 loci with smoking behaviors. Understanding the biological mechanisms through which these genes impact smoking behavior may provide novel insights into the underlying biological mechanisms responsible for the use of tobacco products. It is well known that nicotine is the main psychoactive component in tobacco and is responsible for many of the effects of smoking, from initial reward to many aspects of withdrawal. Its mechanism of action generally is attributed to its action on nicotinic acetylcholine receptors (nAChRs) on neurons. However, astrocytes also express nAChRs and may play a role in nicotine dependence. Accumulating evidence indicates that astrocytes actively participate in behavioral responses to nicotine and nicotine abstinence in both animal models and humans. Therefore, some genes associated with nicotine behaviors in humans may impact these behaviors by altering astrocyte function. Because little is known about the role of astrocytes in nicotine behaviors, this project aims to use an astrocyte in vitro functional assay in the R21 phase to functionally assess and prioritize nicotine GWAS genes that may contribute to nicotine behaviors through their actions in astrocytes. The genes of interest will be validated in vivo following nicotine exposure as an initial GO NO-GO for that gene. Conditional knock-out (cKO) mouse models will then be made for the top two genes identified through the screen, and the GO NO-GO decision will be based on the selectivity and efficiency of removal from astrocytes. The R33 phase will utilize the cKO mice to confirm functional astrocyte effects of the selected genes and assess the specific nicotine phenotypes impacted by targeting these genes selectively in astrocytes. Finally, appropriate brain regions from animals tested will be used for transcriptome studies to identify novel genes and pathways in astrocytes differentially affected by genotype or nicotine exposure. Our approach is conceptually and technically innovative because we will be the first to test the idea that astrocyte culture can be used to functionally assess the role of GWAS- identified genes in nicotine-related neurobiology. We will utilize novel genetic reagents to target GOIs in astrocytes in the brain specifically. This study is also the first to use transcriptomics to address questions of GOI function in nicotinic neural responses, specifically in astrocytes. The proposed research is significant because it will provide insight into astrocyte and GWAS identified gene mechanisms related to nicotine use, which has important implications for improved understanding of nicotine neurobiology and developing more effective therapies to help reduce nicotine use and withdrawal symptoms.

项目总结