Genetic and hormonal contributions to sex differences in vulnerability to drug use

遗传和荷尔蒙对吸毒易感性性别差异的影响

基本信息

批准号：
9886536
负责人：
Wendy Jean Lynch
金额：
$ 34.73万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886536
关键词：
Adult Alcohols Behavior Behavioral Bioinformatics Biological Assay Brain Candidate Disease Gene ChIP-seq Chromatin Chronic stress Cocaine Cocaine Dependence Code Cognitive Competence Data Development Dopamine Drug Addiction Drug usage Enzymes Epigenetic Process Estradiol Estrogens Female Four Core Genotypes Gene Expression Genes Genetic Genetic Transcription Goals Gonadal Hormones Gonadal structure Grant Histone Code Hormonal Human Individual Intravenous Knockout Mice Lead Motivation Mus Mutation Neurons Nuclear Nucleus Accumbens Opioid Receptor Ovarian Ovary Pain Pharmaceutical Preparations Phenotype Ploidies Prefrontal Cortex Prevention strategy Preventive Intervention Prosencephalon Regulation Research Research Personnel Rewards Risk Rodent Role Running Self Administration Serotonin Sex Chromosomes Sex Differences Testing Testis Tissues Transposase Woman Work X Chromosome X Inactivation XCL1 gene addiction brain tissue design drug of abuse drug use vulnerability gamma-Aminobutyric Acid gene product gene repression genotypic sex histone demethylase histone modification innovation literate male men mouse model novel overexpression phenomenological models programs response sex transcription factor

Adult Alcohols Behavior Behavioral Bioinformatics Biological Assay Brain Candidate Disease Gene ChIP-seq Chromatin Chronic stress Cocaine Cocaine Dependence Code Cognitive Competence Data Development Dopamine Drug Addiction Drug usage Enzymes Epigenetic Process Estradiol Estrogens Female Four Core Genotypes Gene Expression Genes Genetic Genetic Transcription Goals Gonadal Hormones Gonadal structure Grant Histone Code Hormonal Human Individual Intravenous Knockout Mice Lead Motivation Mus Mutation Neurons Nuclear Nucleus Accumbens Opioid Receptor Ovarian Ovary Pain Pharmaceutical Preparations Phenotype Ploidies Prefrontal Cortex Prevention strategy Preventive Intervention Prosencephalon Regulation Research Research Personnel Rewards Risk Rodent Role Running Self Administration Serotonin Sex Chromosomes Sex Differences Testing Testis Tissues Transposase Woman Work X Chromosome X Inactivation XCL1 gene addiction brain tissue design drug of abuse drug use vulnerability gamma-Aminobutyric Acid gene product gene repression genotypic sex histone demethylase histone modification innovation literate male men mouse model novel overexpression phenomenological models programs response sex transcription factor

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项目摘要

Abstract Sex differences in drug-related behaviors have been well documented and attributed primarily to differences in levels of estrogens in adult men versus women. This program advances the field beyond this hypothesis to examine another important factor, sex chromosome complement, with a focus on X-chromosome genes that escape X-inactivation which are expressed in greater levels in female versus male brains. The four core genotype (FCG) mouse model allows separate analysis of gonadal hormones and sex chromosome complement (XX vs. XY). In Aim 1 these mice will be used to examine combined and separate actions of estradiol and sex chromosome complement on vulnerability to cocaine addiction using intravenous self- administration. Rates of acquisition and levels of motivation to obtain the drug will be evaluated. In Aim 2, we will define the role of two X-chromosome genes that escape inactivation in mouse and human brain, Utx and Smcx. These genes code for enzymes that demethylate histone modifications, regulating chromatin accessibility and transcription on a wide basis. This work will be conducted with two lines of inducible, tissue- specific knockout mice that lack the expression of either gene (Utx or Smcx) in CaMK2α in forebrain, including neurons in the nucleus accumbens. The mice will be tested as in Aim 1 for cocaine vulnerability and motivation. In Aim 3 brain tissue from the nucleus accumbens of mice tested in Aims 1 and 2 will be used for epigenetic analysis. A combination of ATAC (Assay for Transposase Accessible Chromatin-), Pro (Precision Nuclear Run-On-) and ChIP (Chromatin Immuno-Precipitation-) Sequencing will be used to identify transcriptionally active and repressed genes associated with chromatin restructuring and important transcription factors. The long term objective of this work is to reveal new mechanisms that underlie sex differences in vulnerability to addiction that help clinicians design sex-specific preventions/interventions.

抽象的与药物相关行为的性别差异已得到充分证明，主要归因于差异成年男性与女性的雌激素水平。该计划超越了这个假设的领域为了检查另一个重要因素，性别染色体的完成，重点是X染色体基因逃避X灭活，在雌性大脑和雄性大脑中以更大的水平表达。四个核心基因型（FCG）小鼠模型允许单独分析性腺激素和性染色体补充（xx vs. xy）。在AIM 1中，这些小鼠将用于检查合并和单独的动作雌二醇和性别染色体完成对可卡因成瘾的脆弱性，使用静脉内自我行政。将评估获取率和获得药物的动机水平。在AIM 2中，我们将定义两个X染色体基因在小鼠和人脑，UTX和 SMCX。这些基因代码用于脱甲基化组蛋白修饰的酶，调节染色质可访问性和转录广泛。这项工作将使用两条诱导的组织 - 特定的基因敲除小鼠在前脑中缺乏CAMK2α基因（UTX或SMCX）的表达，包括伏隔核中的神经元。小鼠将在可卡因脆弱性和目标1中进行测试动机。在AIM 3中，在AIM 1和2中测试的小鼠的伏核核组织将用于表观遗传分析。 ATAC（用于转座酶可访问的染色质 - ）的组合，Pro（精度将使用核跑 - ）和CHIP（染色质免疫 - 沉淀 - ）测序识别转录活性和反射的基因与染色质休息和重要转录因子。这项工作的长期目标是揭示基于性的新机制脆弱性的脆弱性差异可以帮助临床医生设计特定的预防/干预措施。