Alcohol-Induced Neuroinflammation and AUD Therapeutic Mechanisms

酒精引起的神经炎症和 AUD 治疗机制

• 批准号: 10580663
• 负责人: Vez REPUNTE-CANONIGO
• 金额: $ 40.73万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580663
• 关键词: Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Anti-Inflammatory Agents; Astrocytes; Biochemical; Carbenoxolone; Chronic; Complex; Effectiveness; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Gene Expression; Gene Expression Regulation; Genetic; Glucocorticoid Receptor; Glucocorticoids; Heavy Drinking; Human; Immunohistochemistry; Inflammasome; Inflammation; Inflammatory; Link; Microglia; Mifepristone; Modeling; Molecular; Monitor; Motivation; Neurobiology; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Positioning Attribute; Probenecid; Proteins; Rattus; Receptor Activation; Receptor Signaling; Regulation; Reverse engineering; Role; Self Administration; Signal Transduction; Systems Biology; TLR4 gene; Techniques; Testing; Therapeutic; Tissues; Treatment Efficacy; Western Blotting; Work; alcohol effect; alcohol use disorder; attenuation; base; drug action; drug candidate; gene regulatory network; inhibitor; neuroinflammation; new therapeutic target; pharmacologic; predictive modeling; public health relevance; receptor; recruit; research clinical testing; targeted treatment; therapeutic target; therapeutically effective; transcriptome sequencing; virtual

Abstract Alcohol use disorder (AUD) is a heterogeneous condition resulting from the interplay of neurobiological, genetic, and environmental factors. There is pressing need to develop new and, potentially, broadly effective medications. Alcohol is a highly pro-inflammatory molecule, which is key in the pathogenesis of alcohol- induced tissue damage. Work by the applicants and collaborators has identified 3 candidate drugs for repositioning for AUD that are likely to act at least in part via reduction of neuroinflammation. They include inhibitors of the pannexin1 channel, which has emerged as a major driver of neuroinflammation, and modulators of glucocorticoid signaling, that has a complex action on inflammation. In fact, chronic glucocorticoids result in neuroinflammation and neuronal damage that contribute to both AUD and neurodegenerative diseases. Collectively, these considerations support targeting inflammation and the associated tissue damage for AUD. However, some inflammatory signaling mechanisms recruited by alcohol, such as the Toll-like receptor 4, have proven not to modify alcohol intake. Thus, it is paramount to delineate the inflammatory mechanisms of motivational and therapeutic significance. To this end, Specific Aim 1 in the present proposal will test the effects of representative anti-inflammatory drugs including direct and indirect inflammasome inhibitors with different mechanisms of action in an established rat paradigm of non-dependent and dependent alcohol intake, which is characterized by escalated alcohol drinking and is highly translational as it proved sensitive to the action of virtually all drugs that have shown promise in human AUD. Interlinked studies in Specific Aim 2 will dissect the effects of alcohol and the therapeutics under study on neuroinflammation, inflammasome regulation and astrocyte and microglia regulation to identify key indicators of alcohol-induced neuroinflammation as well as the mechanisms of action of the drugs under testing to determine the molecular bases of their effectiveness or lack thereof as well as to uncover potential new therapeutic targets for AUD. Altogether, the results of this study will advance our understanding of the mechanisms behind treatment responsiveness or lack thereof as well as of alcohol-induced tissue damage of therapeutic significance, and will point to new therapeutic targets for more specific and effective medications to ameliorate neuroinflammation and tissue damage in the setting of AUD and reduce excessive alcohol consumption.

摘要 酒精使用障碍(AUD)是一种由神经生物学、 遗传和环境因素。迫切需要开发新的，潜在的，广泛有效的 药物。酒精是一种高度促炎的分子，在酒精的发病机制中起着关键作用。 导致组织损伤。申请者和合作者的工作已经确定了3种候选药物 对AUD进行重新定位，这可能至少部分通过减少神经炎症起作用。它们包括 PAnnexin1通道的抑制剂，它已成为神经炎症的主要驱动因素，以及 糖皮质激素信号的调节剂，对炎症有复杂的作用。事实上，慢性 糖皮质激素导致神经炎症和神经元损伤，导致AUD和AUD 神经退行性疾病。总而言之，这些考虑因素支持针对炎症和 与澳元相关的组织损伤。然而，酒精招募的一些炎症信号机制， 例如Toll样受体4，已经被证明不会改变酒精摄入量。因此，至关重要的是要描述 炎症机制具有激励和治疗意义。为此，《公约》中的具体目标1 目前的提案将测试具有代表性的抗炎药物的效果，包括直接和间接 不同作用机制的炎性小体抑制剂在已建立的非依赖性大鼠模型中的作用 以及依赖酒精摄入，其特征是饮酒增加，具有高度的翻译性 因为它被证明对几乎所有在人类AUD中显示出希望的药物的作用敏感。相互关联的 具体目标2的研究将剖析酒精的影响和正在研究的治疗方法。 神经炎症、炎症体调节以及星形胶质细胞和小胶质细胞调节以确定关键指标 酒精引起的神经炎症以及被测试药物的作用机制 确定其有效性或缺乏的分子基础，以及发现潜在的新 AUD的治疗靶点。 总之，这项研究的结果将促进我们对治疗背后的机制的理解。 反应性或缺乏反应性以及酒精引起的具有治疗意义的组织损伤，以及 将指向新的治疗靶点，寻找更具体和有效的药物来改善 在AUD的背景下，神经炎症和组织损伤，减少过度饮酒。