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.

项目摘要/摘要 存在与药物滥用障碍有关的基于性别的差异，临床前和 临床研究。女性通常更容易受到启动，升级和戒断的影响 药物滥用行为比男性。尽管这些差异在很大程度上归因于荷尔蒙 差异，非激素因素调节成瘾的证据已得到许多 研究。但是，性别染色体对药物滥用行为的影响的机制 在我们关于物质使用障碍的表观遗传学的知识基础上代表了一个巨大的差距。我们提出了一本小说 从女性中逃脱X染色体灭活（XCI）的假设有助于性相关 成瘾行为的差异。我们将采用尖端技术和独特的新颖方法， 我们最近开发的工具，以全面研究XCI逃生对性别相关性的影响 成瘾中的差异。 XCI是一种表观遗传机制，发生在哺乳动物的女性中，用于 均衡性别之间的基因表达。女性有两个X染色体（XX），在XCI期间，一个X 随机选择染色体被转录沉默。但是，众所周知，许多X链接 基因逃脱XCI并显示BI等位基因表达。该提议的目的是确定 XCI逃脱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 尖端小鼠模型以表征细胞单相（XCI）或BI-callelic（XCI逃逸）基因表达 与阿片类药物和精神刺激剂成瘾有关的特定X连锁基因：单胺氧化酶A （MAOA）和GABAA受体A3（Gabra3）。我开创了一种创新的方法，该方法使用基因特异性双重双重 Cistronic Reporter鼠标作为一种工具，可以使这些成瘾相关基因的等位基因使用可视化 体内成瘾模型。接下来，我们将确定脑组织中XCI的分子景观和特定 长期暴露于阿片类药物和精神刺激剂的神经元细胞，使用高度创新的单细胞 RNA测序技术。为了实现这些目标，我组建了一个有才华的多学科团队 研究合作者成瘾，神经科学，遗传小鼠建模，生物信息学和生物统计学。 对基因特异性XCI的研究和分析的这种创新方法，作为一种表观遗传机制 药物滥用的背景有可能开放有关表观遗传学的新研究领域 瘾。此外，这些转基因的小鼠可用于研究XCI逃脱作为表观遗传机制 在其他神经系统疾病中。作为早期研究者，这些研究也将提高我的长期 成为物质使用障碍表观遗传学的未来领导者的目标。

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