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; 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.

抽象的 酒精使用障碍（AUD）是由神经生物学的相互作用导致的异质疾病 遗传和环境因素。有迫切需要开发新的，可能是广泛有效的 药物。酒精是一种高度促炎的分子，它是酒精发病机理的关键 诱导组织损伤。申请人和合作者的工作已经确定了3种候选药物 重新定位AUD至少部分通过减少神经炎症而起作用。它们包括 pannexin1通道的抑制剂已成为神经炎症的主要驱动力，并且 糖皮质激素信号传导的调节剂，对炎症具有复杂的作用。实际上，慢性 糖皮质激素会导致神经炎症和神经元损伤，这既有助理和 神经退行性疾病。总的来说，这些考虑因素支持针对炎症和 AUD的相关组织损伤。但是，酒精招募的某些炎症信号传导机制， 如Toll样受体4，已被证明不改变酒精摄入量。因此，描绘的至关重要 动机和治疗意义的炎症机制。为此，具体目标1 目前的建议将测试代表性抗炎药的影响，包括直接和间接 在已建立的非依赖性大鼠范式中具有不同作用机制的炎性抑制剂 和依赖的酒精摄入量，其特征是饮酒升级，并且是高度翻译的 事实证明，它对几乎所有在人类声音中表现出希望的药物的作用敏感。相互联系 特定目标2中的研究将剖析酒精和正在研究的治疗剂对 神经炎症，炎性体调节以及星形胶质细胞和小胶质细胞调节，以识别关键指标 酒精引起的神经炎症以及正在测试的药物的作用机理 确定其有效性或缺乏其有效性的分子碱基，并发现潜力新 AUD的治疗目标。 总之，这项研究的结果将提高我们对治疗机制的理解 反应性或缺乏其治疗意义的组织损害，并且 将指出新的治疗靶标，以改善更具体和有效的药物 在AUD的情况下，神经炎症和组织损伤并减少过度饮酒。