Genetic basis of nicotine withdrawal in a reduced complexity cross

降低复杂性杂交中尼古丁戒断的遗传基础

• 批准号: 10401810
• 负责人: M. Imad Damaj
• 金额: $ 55.42万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401810
• 关键词: Affective; Aftercare; Alleles; Amygdaloid structure; Animal Model; Behavior; Behavioral; Biological; Brain region; CRISPR/Cas technology; Candidate Disease Gene; Cell Nucleus; Cessation of life; Chronic; Complex; Data; Development; Etiology; Female; Future; Gene Targeting; Genes; Genetic; Genetic Variation; Genetic study; Genome; Genomic Segment; Genomics; Health; Human; Human Genome; Individual; Lead; Maps; Measures; Mediating; Modeling; Molecular; Mus; Neurobiology; Neuronal Plasticity; Neurons; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nucleus Accumbens; Pathway Analysis; Pathway interactions; Phenotype; Predisposition; Publishing; Quantitative Trait Loci; Relapse; Saline; Smoking; System; Time; Tissue-Specific Gene Expression; Tissues; Tobacco; Tobacco smoking behavior; Variant; Withdrawal; base; behavior change; candidate validation; differential expression; epidemiologic data; gene function; gene network; genetic architecture; genetic variant; genome editing; insight; mRNA sequencing; male; mouse genome; mouse model; nicotine abuse; nicotine cessation; nicotine exposure; nicotine use; novel; novel therapeutics; null mutation; resilience; response; smoking addiction; smoking cessation; therapy development; tool; trait; transcriptome; transcriptome sequencing; translational genetics

Project Summary Despite evidence of strong genetic contributions to the etiology of nicotine dependence (ND), we are far from identifying the specific genetic bases of individual susceptibility to ND. The primary objective of this proposal is to identify novel genetic factors that contribute to nicotine withdrawal, an important aspect of ND that contribute relapse, in mice. We observed pronounced nicotine withdrawal traits differences in C57BL/6NJ strain but not in the closely related C57BL/6J substrain. Because the parental substrains are nearly genetically identical, quantitative trait locus (QTL) mapping in an experimental F2 cross (Reduced Complexity Cross; RCC) will greatly facilitate the identification of novel genetic factors that underlie differences in withdrawal behaviors. In Aim 1, we will use the RCC to map genomic regions, or QTLs, that are causally associated with susceptibility versus resilience to multiple measures of nicotine withdrawal. In Aim 2, we will conduct transcriptome analysis via mRNA sequencing (RNA-seq) of four brain regions regions in control mice and chronic nicotine-treated mice from the parental male and female C57BL/6J and C57BL/6NJ substrains. The transcriptome in control mice will serve as a useful tool both in identifying candidate genes for future genome editing that are differentially expressed and underlie the behavioral QTLs as well as providing genomic insight into the neuronal context that influences susceptibility versus resilience to nicotine withdrawal. Genes that are differentially expressed as a consequence of nicotine will reveal changes in the transcriptome relevant to central neuronal plasticity and the behaviors/changes that support ND. In Aim 3, we will validate candidate quantitative trait genes and functional variants identified and ranked by Aims 1-2.

项目总结

项目成果

Characterization of single nucleotide polymorphisms for a forward genetics approach using genetic crosses in C57BL/6 and BALB/c substrains of mice.

使用C57BL/6和小鼠BALB/C基质中的遗传杂交的单核苷酸多态性的表征。

• DOI: 10.1538/expanim.21-0181
• 发表时间: 2022-05-20
• 期刊: EXPERIMENTAL ANIMALS
• 影响因子: 2.4
• 作者: Miura, Ikuo;Kikkawa, Yoshiaki;Yasuda, Shumpei P.;Shinogi, Akiko;Usuda, Daiki;Kumar, Vivek;Takahashi, Joseph S.;Tamura, Masaru;Masuya, Hiroshi;Wakana, Shigeharu
• 通讯作者: Wakana, Shigeharu