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: 10461142
• 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461142
• 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; stimulant use; 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.

项目概要/摘要 药物滥用障碍存在基于性别的差异，临床前和临床研究就证明了这一点。 临床研究。女性通常更容易受到启动、升级和退出效应的影响 药物滥用行为高于男性。尽管这些差异很大程度上归因于荷尔蒙 尽管存在差异，但许多研究已经证明了调节成瘾的非激素因素的证据 研究。然而，性染色体影响药物滥用行为的机制 代表了我们在物质使用障碍表观遗传学知识基础上的巨大差距。我们提议写一本小说 假设女性逃避 X 染色体失活（XCI）有助于性别相关 成瘾行为的差异。我们将应用尖端技术和独特的新颖方法 我们最近开发的工具用于全面调查 XCI 逃逸对性相关的影响 成瘾程度的差异。 XCI 是一种发生在雌性哺乳动物中的表观遗传机制，用于 使两性之间的基因表达均衡。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，众所周知，许多X连锁 基因逃避 XCI 并显示双等位基因表达。该提案的目的是确定 XCI 逃逸对药物滥用障碍性别相关差异的贡献。首先，我们将使用小说 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 (Gabra3)。我开创了一种创新方法，使用基因特异性双双 顺反子报告小鼠作为工具，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 在脑组织中的分子格局和具体情况 长期接触阿片类药物和精神兴奋剂期间的神经元细胞，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 成瘾、神经科学、基因小鼠建模、生物信息学和生物统计学领域的研究合作者。 这种创新方法用于研究和分析基因特异性 XCI 逃逸作为表观遗传机制 药物滥用的背景有可能开辟一个新的表观遗传学研究领域 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 在其他神经系统疾病中。作为一名早期研究人员，这些研究也将推动我的长期发展 目标是成为物质使用障碍表观遗传学的未来领导者。

项目成果

STAT1 is regulated by TRIM24 and promotes immunosuppression in head and neck squamous carcinoma cells, but enhances T cell antitumour immunity in the tumour microenvironment.

• DOI: 10.1038/s41416-022-01853-z
• 发表时间: 2022-09
• 期刊: BRITISH JOURNAL OF CANCER
• 影响因子: 8.8
• 作者: Anderson, Kelvin;Ryan, Nathan;Nedungadi, Divya;Lamenza, Felipe;Swingler, Michael;Siddiqui, Arham;Satoskar, Abhay;Upadhaya, Puja;Pietrzak, Maciej;Oghumu, Steve
• 通讯作者: Oghumu, Steve

Black raspberry extract inhibits regulatory T-cell activity in a murine model of head and neck squamous cell carcinoma chemoprevention.

• DOI: 10.3389/fimmu.2022.932742
• 发表时间: 2022
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Ryan, Nathan M.;Lamenza, Felipe F.;Upadhaya, Puja;Pracha, Hasan;Springer, Anna;Swingler, Michael;Siddiqui, Arham;Oghumu, Steve
• 通讯作者: Oghumu, Steve

Sex differences in susceptibility to substance use disorder: Role for X chromosome inactivation and escape?

• DOI: 10.1016/j.mcn.2023.103859
• 发表时间: 2023-05-24
• 期刊: MOLECULAR AND CELLULAR NEUROSCIENCE
• 影响因子: 3.5
• 作者: Krueger，Kate;Lamenza，Felipe;Oghumu，Steve
• 通讯作者: Oghumu，Steve