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：
10549291
负责人：
Wendy Jean Lynch
金额：
$ 54.31万
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/10549291
关键词：
Adult Alcohols Behavior Behavioral Bioinformatics Biological Assay Brain Candidate Disease Gene 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 Intervention Intravenous Knockout Mice Lead Motivation Mus Mutation Neurons Nuclear Nucleus Accumbens Opioid Receptor Ovarian Ovary Pain Pharmaceutical Preparations Phenotype Ploidies Prefrontal Cortex Prevention Prevention strategy 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 addiction brain tissue chromatin immunoprecipitation cocaine self-administration demethylation 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

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.

抽象的毒品相关行为的性别差异已得到充分记录，并主要归因于差异该项目在成年男性与女性的雌激素水平方面取得了进展，超越了这一假设。检查另一个重要因素，性染色体补体，重点关注 X 染色体基因逃避 X 失活的基因在女性大脑中的表达水平高于男性。基因型 (FCG) 小鼠模型可单独分析性腺激素和性染色体补体（XX 与 XY）在目标 1 中，这些小鼠将用于检查的组合和单独作用。雌二醇和性染色体互补对可卡因成瘾的脆弱性使用静脉自我在目标 2 中，我们将评估获取率和获取药物的动机水平。将定义小鼠和人类大脑中逃脱失活的两个 X 染色体基因 Utx 和 Smcx.这些基因编码使组蛋白修饰去甲基化、调节染色质的酶。这项工作将在广泛的基础上使用两条诱导型组织细胞系进行。前脑 CaMK2α 基因（Utx 或 Smcx）表达缺失的特定敲除小鼠，包括小鼠伏隔核中的神经元将按照目标 1 进行可卡因脆弱性和在目标 3 中，来自目标 1 和目标 2 中测试的小鼠伏隔核的脑组织将用于研究动机。表观遗传分析。ATAC（转座酶可及染色质检测）、Pro（精密度检测）的组合。核运行 (Nuclear Run-On) 和 ChIP（染色质免疫沉淀）测序将用于鉴定与染色质重组相关的转录活性和抑制基因以及重要的这项工作的长期目标是揭示性行为的新机制。成瘾脆弱性的差异有助于设计针对特定性别的预防/干预措施。