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

基本信息

批准号：
10371484
负责人：
Collin Merrill
金额：
$ 15.62万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10371484
关键词：
Acute Affect Alcohol abuse Alcohol consumption Alcoholic Intoxication Alcohols Binding Sites Bioinformatics Biological Assay Biological Models Brain Cells Cellular Assay 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 base 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

项目摘要

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.

酗酒影响数百万人，每年导致多人死亡。那些人抵抗性酒精中毒和镇静更有可能消耗大量酒精（暴饮暴食）饮酒）并且患酒精使用障碍的风险较高。其背后的一种机制酒精使用障碍的发生是神经元的可塑性，涉及基因的调节表达。 GABA 能神经元中染色质介导的基因调控如何导致酒精中毒引起的镇静和耐受性尚不清楚。我使用转座酶测定的初步数据- 可访问染色质测序 (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传导相关的基因。我建议研究 ATAC-seq 确定的相关神经元通路，以评估染色质如何重塑影响酒精镇静和耐受性。此外，我的初步数据表明酒精改变 GABA 神经元的基因调控，尤其是在胰岛素受体中发挥作用的基因途径。最后，我建议识别 GABA 神经元亚型并开发遗传工具，以允许亚型特异性操作，然后将用于研究 GABA 神经元亚型如何涉及酒精使用障碍。这些活动将确定酒精的潜在治疗靶点使用障碍。虽然我有单神经元生理学方面的经验，但我需要额外的培训才能成为一名成功的独立调查员。因此，我的近期职业目标是获得校外资助并撰写手稿，以建立酒精相关研究的专业知识。我的长期职业目标是成为一名独立研究者并建立成功的研究研究 GABA 能神经元在酒精使用障碍中的作用的计划。该提案利用了我之前接受过单神经元生理学方面的培训，并将提供广泛的额外培训果蝇模型系统、酒精滥用机制和生物信息学分析。我预计每个目标将产生至少两份科学手稿，并为未来提供初步数据 R01应用。因此，完成此处建议的活动将使我能够过渡到独立首席研究员。