Chromatin remodeling in GABA neurons contributes to alcohol use disorder

酒精滥用影响着数百万人，每年导致许多人死亡。的人 抵抗酒精中毒和镇静更有可能消耗高水平的酒精（狂欢 饮酒），并有更高的风险发展酒精使用障碍。一种潜在的机制 酒精使用障碍的发展是神经元可塑性，这涉及基因的调节， 表情GABA能神经元中染色质介导的基因调控如何促进酒精- 诱导的镇静和耐受性未知。我的初步数据使用转座酶测定- 通过测序（ATAC-seq）的染色质图谱显示，GABA中的染色质图谱 神经元被酒精暴露改变，特别是与胰岛素受体信号相关的基因。 我建议研究通过ATAC-seq鉴定的相关神经通路，以评估染色质 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 通路最后，我建议识别GABA神经元亚型，并开发遗传工具， 亚型特异性操作，然后将用于研究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，但我需要额外的训练， 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 校外资助和生产手稿，以建立酒精相关研究的专业知识。我 长期的职业目标是成为一名独立的研究者，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。该提案利用了 我以前在单神经元生理学方面的训练，并将提供广泛的额外训练， 果蝇模型系统、酒精滥用机制与生物信息学分析。我预计 每个目标将产生至少两份科学手稿，并将为今后的研究提供初步数据， R 01应用程序。因此，完成此处提出的活动将使我能够过渡到 独立首席调查员

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.