X chromosome inactivation in sex disparities to substance use disorder

X 染色体失活导致性别差异导致药物滥用障碍

• 批准号: 10293214
• 负责人: Steve Onyeka Oghumu
• 金额: $ 47.25万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10293214
• 关键词: Alleles; Area; Behavior; Bioinformatics; Biometry; Cells; Chronic; Clinical Research; Disease; Epigenetic Process; Exposure to; Female; Future; Gene Expression; Gene Silencing; Genes; Genetic; Goals; Hormonal; Link; Modeling; Molecular; Monoamine Oxidase A; Mus; Neurons; Neurosciences; Opioid; Public Health; Reporter; Research; Research Personnel; Sex Chromosomes; Sex Differences; Substance Use Disorder; Substance abuse problem; Talents; Technology; Visualization; Withdrawal; X Chromosome; X Inactivation; addiction; base; brain tissue; in vivo; innovation; knowledge base; male; mouse model; multidisciplinary; nervous system disorder; novel; novel strategies; preclinical study; psychostimulant; receptor; sex; sex disparity; single-cell RNA sequencing; tool

PROJECT SUMMARY/ABSTRACT There is a sex-based disparity associated with substance abuse disorders, which is evidenced by preclinical and clinical studies. Females are generally more vulnerable to the initiation, escalation and withdrawal effects of substance abuse behavior than males. Although these differences have largely been attributed to hormonal differences, evidence for non-hormonal factors that regulate addiction has been demonstrated by a number of studies. However, the mechanisms underlying sex chromosome influences on substance abuse behavior represent a huge gap in our knowledge base on the epigenetics of substance use disorders. We propose a novel hypothesis that escape from X-chromosome inactivation (XCI) in females contributes to sex associated differences in addiction behavior. We will apply cutting edge technology and uniquely novel approaches and tools we developed recently to comprehensively investigate the impact of XCI escape on sex associated disparities in addiction. XCI is an epigenetic mechanism that occurs in mammalian females and serves to equalize gene expression between the sexes. Females have two X chromosomes (XX), and during XCI, one X chromosome is randomly chosen to be transcriptionally silenced. However, it is known that a number of X linked genes escape XCI and display bi allelic gene expression. The objective of this proposal is to determine the contribution of XCI escape on sex-associated differences in substance abuse disorder. First, we will use novel cutting edge mouse models to characterize cellular mono-allelic (XCI) or bi-allelic (XCI escape) gene expression of specific X-linked genes associated with addiction to opioids and psychostimulants: monoamine oxidase A (Maoa) and GABAA receptor A3 (Gabra3). I pioneered an innovative approach using a gene specific dual bi- cistronic reporter mouse as a tool to enable the visualization of allelic usage of these addiction associated genes in vivo in a model of addiction. Next, we will determine the molecular landscape of XCI in brain tissue and specific neuronal cells during chronic exposure to opioids and psychostimulants, using a highly innovative single cell RNA sequencing technology. To accomplish these goals, I have assembled a talented, multidisciplinary team of research collaborators in addiction, neuroscience, genetic mouse modelling, bioinformatics and biostatistics. This innovative approach to the study and analysis of gene specific XCI escape as an epigenetic mechanism in the context of substance abuse has the potential to open up a new area of research on the epigenetics of addiction. Further, these genetically modified mice can be used to study XCI escape as an epigenetic mechanism in other neurologic disorders. As an early stage investigator, these studies will also advance my long term objective of becoming a future leader in the epigenetics of substance use disorders.

项目总结/摘要 存在与物质滥用障碍相关的基于性别的差异，这由临床前和 临床研究。女性通常更容易受到性行为的启动、升级和退出的影响。 药物滥用行为多于男性。虽然这些差异主要归因于荷尔蒙 尽管存在差异，但一些研究已经证明了调节成瘾的非激素因素的证据， 问题研究然而，性染色体影响药物滥用行为的潜在机制 代表了我们在物质使用障碍的表观遗传学知识基础上的巨大差距。我们提出了一种新 女性逃避X染色体失活（XCI）的假说有助于性相关的 成瘾行为的差异。我们将应用尖端技术和独特的新方法， 我们最近开发的工具，全面调查XCI逃逸对性相关的影响， 成瘾的差异。XCI是一种发生在哺乳动物雌性中的表观遗传机制， 使两性之间的基因表达平衡。女性有两条X染色体（XX），在XCI期间，一条X染色体 随机选择染色体进行转录沉默。然而，据了解，一些X链接 基因逃避XCI并显示双等位基因表达。本提案的目的是确定 XCI逃避对物质滥用障碍性别相关差异的贡献首先，我们将使用新的 用于表征细胞单等位基因（XCI）或双等位基因（XCI逃逸）基因表达的尖端小鼠模型 与阿片类药物和精神兴奋剂成瘾相关的特定X连锁基因：单胺氧化酶A （Maoa）和GABAA受体A3（Gabra 3）。我开创了一种创新的方法，使用基因特异性双双- 顺反子报告小鼠作为一种工具，使这些成瘾相关基因的等位基因使用可视化 在体内成瘾模型中。接下来，我们将确定XCI在脑组织中的分子景观和特异性 神经元细胞在慢性暴露于阿片类药物和精神兴奋剂，使用高度创新的单细胞 RNA测序技术。为了实现这些目标，我组建了一支才华横溢的多学科团队， 在成瘾、神经科学、遗传小鼠建模、生物信息学和生物统计学方面的研究合作者。 这种创新的方法来研究和分析基因特异性XCI逃逸作为一种表观遗传机制， 药物滥用的背景有可能开辟一个新的研究领域， 成瘾此外，这些转基因小鼠可用于研究XCI逃逸作为表观遗传机制 其他神经系统疾病作为一名早期研究者，这些研究也将推动我的长期研究。 目标是成为物质使用障碍表观遗传学的未来领导者。