Chromatin remodeling in GABA neurons contributes to alcohol use disorder

GABA 神经元的染色质重塑导致酒精使用障碍

• 批准号: 10569097
• 负责人: Collin Merrill
• 金额: $ 15.71万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569097
• 关键词: ATAC-seq; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Intoxication; Alcohols; Binding Sites; Bioinformatics; Biological Assay; Biological Models; Brain; Cells; Cessation of life; Chromatin; Chromatin Structure; Consumption; Coupled; Data; Development; Disinhibition; Dose; Drosophila genus; Drosophila melanogaster; Economic Burden; Enzymes; Ethanol; Extramural Activities; Funding; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Grant; Human; Individual; Insulin Receptor; Intoxication; Knock-out; Mammals; Manuscripts; Mediating; Modeling; Neuronal Plasticity; Neurons; Neurotransmitters; Orthologous Gene; Pathway interactions; Persons; Physiology; Play; Principal Investigator; Receptor Signaling; Research; Research Personnel; Resistance; Rewards; Risk; Role; Route; Sedation procedure; System; Training; Transposase; United States; alcohol behavior; alcohol effect; alcohol exposure; alcohol measurement; alcohol misuse; alcohol research; alcohol response; alcohol sensitivity; alcohol use disorder; binge drinking; career; chromatin remodeling; experience; fly; gamma-Aminobutyric Acid; high risk; insulin regulation; knock-down; new therapeutic target; preference; programs; response; therapeutic target; tool; transcription factor; vinegar fly

Alcohol misuse affects millions of people, resulting in numerous deaths each year. People who are resistant alcohol intoxication and sedation are more likely to consume high levels of alcohol (binge drinking) and are at higher risk of developing alcohol use disorder. One mechanism underlying the development of alcohol use disorder is neuronal plasticity, which involves the regulation of gene expression. How chromatin-mediated gene regulation in GABAergic neurons contributes to alcohol- induced sedation and tolerance is unknown. My preliminary data using Assay for Transposase- Accessible Chromatin by sequencing (ATAC-seq) shows that the chromatin landscape in GABA neurons is altered by alcohol exposure, particularly in genes associated with insulin receptor signaling. I propose to investigate relevant neuronal pathways identified by ATAC-seq to evaluate how chromatin remodeling affects alcohol sedation and tolerance. Further, my preliminary data indicate that alcohol alters gene regulation in GABA neurons, especially in genes that play a role in the insulin receptor pathway. Finally, I propose to identify GABA neuron subtypes and to develop genetic tools that allow subtype-specific manipulation, which will then be used to investigate how GABA neuron subtypes are involved in alcohol use disorders. These activities will identify potential therapeutic targets for alcohol use disorders. While I have experience in single-neuron physiology, I require additional training to become a successful independent investigator. Thus, my immediate career goals are to obtain extramural funding and produce manuscripts to establish expertise in alcohol-related research. My long-term career goals are to become an independent investigator and establish a successful research program investigating the role of GABAergic neurons in alcohol use disorder. This proposal leverages my previous training in single-neuron physiology and will provide extensive additional training in Drosophila model systems, the mechanisms of alcohol abuse, and bioinformatic analysis. I anticipate that each aim will produce at least two scientific manuscripts and will provide preliminary data for future R01 applications. Therefore, completing the activities proposed here will enable my transition to an independent principal investigator.

酒精滥用影响了数百万人，每年导致无数人死亡。人们是谁 耐酒精中毒和镇静更有可能消耗高水平的酒精(狂欢 饮酒)，患酒精使用障碍的风险更高。一个潜在的机制是 酒精使用障碍的发生与神经元的可塑性有关，涉及基因调控。 表情。染色质介导的GABA能神经元基因调控如何影响酒精 诱导镇静和耐受性尚不清楚。我用转座酶检测的初步数据- 可及染色质测序(ATAC-SEQ)显示GABA中的染色质景观 酒精暴露会改变神经元，特别是与胰岛素受体信号相关的基因。 我建议研究atac-seq确定的相关神经元通路，以评估染色质是如何 重塑会影响酒精镇静和耐受性。此外，我的初步数据显示酒精 改变GABA神经元的基因调控，特别是在胰岛素受体中起作用的基因 路径。最后，我建议确定GABA神经元亚型，并开发基因工具，使 亚型特异性操作，然后将被用来研究GABA神经元亚型是如何 与酒精使用障碍有关。这些活动将确定酒精的潜在治疗靶点。 使用障碍。虽然我在单神经元生理学方面有经验，但我需要额外的培训来 成为一名成功的独立调查员。因此，我目前的职业目标是获得 提供外部资金并制作手稿，以建立与酒精有关的研究的专门知识。我的 长期的职业目标是成为一名独立的调查员，并建立一个成功的研究 研究GABA能神经元在酒精使用障碍中的作用的计划。这项提议充分利用了 我之前在单神经元生理学方面的培训，并将在 果蝇模型系统、酒精滥用机制和生物信息学分析。我期待着 每个目标将产生至少两份科学手稿，并将为未来提供初步数据 R01应用程序。因此，完成这里提出的活动将使我能够过渡到 独立首席调查员。