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.

项目概要 尽管有证据表明遗传因素对尼古丁依赖的病因有很大影响 （ND），我们还远远没有确定个体易感性的具体遗传基础 ND。该提案的主要目标是确定新的遗传因素 导致尼古丁戒断，这是 ND 导致复发的一个重要方面， 老鼠。我们观察到 C57BL/6NJ 中明显的尼古丁戒断特征差异 菌株，但不在密切相关的 C57BL/6J 亚菌株中。因为父母的基因 基因几乎相同，在实验中进行数量性状位点（QTL）定位 F2杂交（Reduced Complexity Cross；RCC）将大大方便鉴定 造成戒断行为差异的新遗传因素。在目标 1 中，我们将 使用 RCC 来绘制基因组区域或 QTL，这些区域与 对多种尼古丁戒断措施的敏感性与抵抗力。在目标 2 中，我们 将通过 mRNA 测序 (RNA-seq) 对四个大脑进行转录组分析 对照小鼠和来自亲本雄性的慢性尼古丁治疗小鼠的区域 以及雌性 C57BL/6J 和 C57BL/6NJ 亚系。对照小鼠的转录组将 作为一个有用的工具，可以识别未来基因组编辑的候选基因 差异表达，是行为 QTL 的基础，并提供 对影响易感性与弹性的神经元环境的基因组洞察 尼古丁戒断。差异表达的基因 尼古丁将揭示与中枢神经元可塑性相关的转录组的变化 以及支持 ND 的行为/变化。在目标 3 中，我们将验证候选人 按目标 1-2 鉴定和排序数量性状基因和功能变异。

项目成果

Investigating the role of nicotinic acetylcholine receptors in menthol's effects in mice.

研究烟碱乙酰胆碱受体在薄荷醇对小鼠的作用中的作用。

• 发表时间: 2024-04-01
• 影响因子: 4.2
• 作者: Akinola, Lois S;Gonzales, Jada;Buzzi, Belle;Mathews, Hunter L;Papke, Roger L;Stitzel, Jerry A;Damaj, M Imad
• 通讯作者: Damaj, M Imad

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 BALB/c 小鼠亚系的遗传杂交来表征正向遗传学方法的单核苷酸多态性。

• 发表时间: 2022-05-20
• 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