Ethanol-Induced Reactive Astrocytes and Recovery

乙醇诱导的反应性星形胶质细胞和恢复

• 批准号: 10607563
• 负责人: Steven Guerin
• 金额: $ 3.82万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10607563
• 关键词: Abstinence; Affect; Alcohol Phenotype; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Astrocytes; Birth; Brain; Cells; Characteristics; Cognitive deficits; Data Science; Dependence; Development; Down-Regulation; Drug Targeting; Environment; Equilibrium; Ethanol; Exhibits; Faculty; Gene Expression; Glutamate Receptor; Glutamate Transporter; Glutamates; Goals; Growth Factor; Heavy Drinking; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Individual; Instruction; Intermediate Filaments; Intoxication; Ions; Link; Mentors; Mentorship; Modeling; Molecular; Morphology; Nerve Degeneration; Neuraxis; Neuroglia; Neurons; Neuropathogenesis; Neurotransmitters; Parahippocampal Gyrus; Pathologic; Pathology; Pattern; Pharmacology; Phenotype; Play; Process; Proteins; Rattus; Recovery; Research; Research Personnel; Role; Science; Scientific Advances and Accomplishments; Source; Stimulus; Structure; Techniques; Training; adult neurogenesis; alcohol abstinence; alcohol exposure; alcohol use disorder; brain volume; career; career development; cognitive function; cognitive recovery; dentate gyrus; druggable target; experience; experimental study; extracellular; glutamatergic signaling; immunohistochemical markers; improved; insight; interest; large datasets; nerve stem cell; neurogenesis; neuron loss; neurotransmitter release; receptor; recruit; response; stem cells; symposium; training project; undergraduate student; uptake

Project Summary Individuals with Alcohol Use Disorder (AUD) frequently experience cognitive deficits, which are believed to be related to alcohol-induced corticolimbic damage. Following abstinence from alcohol, individuals can recover some function, but the mechanism behind this process is poorly understood. Astrocytes, glial cells which perform numerous important homeostatic functions in the brain, exhibit phenotypic changes following exposure to ethanol in animal models. Astrocyte reactivity is highly pathology specific, and many of the characteristics of this reactivity have not been studied in detail using an animal model of alcohol dependence and neurodegeneration. Evidence collected thus far indicates that this reactivity results in changes to astrocyte structure and precedes a burst in neurogenesis seen in abstinence. Given the role of astrocytes in releasing neurotransmitters and growth factors, these alcohol-induced reactive astrocytes might play an important role in recovery from AUD. This project will utilize two aims to first describe the phenotype of these astrocytes, and then probe a possible mechanism for their role in recovery. In both aims, rats will be exposed to ethanol, in a model which mimics the intoxication, dependence, and neurodegeneration experienced by humans with AUD. In Aim 1, a multi-faceted approach will be utilized to describe astrocyte morphology, proteins of interest that may be involved in recovery, and gene expression. In Aim 2, a pharmacologic approach will be taken to modulate glutamate signaling in astrocytes, to understand how this facet of phenotypic change may affect neurogenesis and recovery from AUD. Training: This project will significantly advance the training goals of the applicant by providing instruction in advanced scientific techniques and professional development to help the applicant achieve his career goal of becoming an independent researcher. Training in data science classes, accompanied by faculty mentorship, will assist with analyzing large data sets needed to complete this project. Professional development training will include undergraduate mentoring, presentation of science both internally and at conferences, research conduct training, and career development opportunities.

项目概要 患有酒精使用障碍 (AUD) 的人经常会出现认知缺陷，这被认为是 与酒精引起的皮质边缘损伤有关。戒酒后，个人可以康复 一些功能，但这个过程背后的机制却知之甚少。星形胶质细胞、神经胶质细胞执行 大脑中许多重要的稳态功能在接触乙醇后表现出表型变化 在动物模型中。星形胶质细胞反应性具有高度病理学特异性，并且这种反应性的许多特征 尚未使用酒精依赖和神经退行性变的动物模型进行详细研究。证据 迄今为止收集的数据表明，这种反应性会导致星形胶质细胞结构的变化，并先于星形胶质细胞的爆发 禁欲时可见神经发生。鉴于星形胶质细胞在释放神经递质和生长因子方面的作用， 这些酒精诱导的反应性星形胶质细胞可能在 AUD 的恢复中发挥重要作用。该项目将 利用两个目标首先描述这些星形胶质细胞的表型，然后探讨可能的机制 他们在康复中的作用。在这两个目标中，老鼠将在模拟中毒的模型中接触乙醇， AUD 患者经历的依赖性和神经退行性变。在目标 1 中，将采取多方面的方法 用于描述星形胶质细胞形态、可能参与恢复的感兴趣的蛋白质以及基因 表达。在目标 2 中，将采用药理学方法来调节星形胶质细胞中的谷氨酸信号传导，以 了解表型变化的这一方面如何影响 AUD 的神经发生和恢复。训练： 该项目将通过提供高级指导来显着推进申请人的培训目标 科学技术和专业发展，帮助申请人实现成为一名 独立研究员。数据科学课程培训以及教师指导将有助于 分析完成该项目所需的大型数据集。专业发展培训将包括 本科生指导、内部和会议上的科学介绍、研究行为培训、 和职业发展机会。