Pathogenesis of Early- Versus Late-Stage Alcohol-Mediated White Matter Degeneration

早期与晚期酒精介导的白质变性的发病机制

• 批准号: 10426054
• 负责人: SUZANNE M. DE LA MONTE
• 金额: $ 34.56万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426054
• 关键词: Abstinence; Acute; Address; Adverse effects; Agonist; Alcohol abuse; Alcohols; Anabolism; Atrophic; Autopsy; Axon; Biochemical; Biological Assay; Brain; Brain Diseases; Cell Survival; Cell membrane; Cellular Assay; Cellular Structures; Ceramides; Cerebrum; Chronic; Cognitive deficits; Data; Disease; Electron Microscopy; Ensure; Enzyme-Linked Immunosorbent Assay; Enzymes; Ethanol; Exhibits; Experimental Models; FRAP1 gene; Female; Functional disorder; Gene Expression; Goals; Homeostasis; Human; Immunohistochemistry; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Antagonists; Insulin-Like Growth Factor I; Intervention; Lead; Link; Lipid Peroxidation; Lipids; Long-Term Effects; Longevity; Maintenance; Mediating; Membrane Lipids; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular Abnormality; Monitor; Myelin; Nerve Degeneration; Neurocognitive; Neuronal Plasticity; Neurons; Oligodendroglia; Oxidative Stress; PPAR delta; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peripheral Blood Mononuclear Cell; Population; Rattus; Reporting; Research; Research Design; Role; Signal Pathway; Signal Transduction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sphingolipids; Stress; Structure; Sulfoglycosphingolipids; Therapeutic; Time; alcohol effect; alcohol exposure; alcohol monitoring; axon injury; axonal degeneration; binge drinking; brain cell; cell type; cognitive function; effectiveness evaluation; enzyme activity; experimental study; feeding; human model; indexing; inhibitor; insulin sensitizing drugs; lipid metabolism; liver injury; male; mass spectrometric imaging; molecular pathology; myelin degeneration; neurobehavioral; neurotoxic; non-invasive monitor; novel; prevent; receptor; relative effectiveness; response; restoration; sex; thermozymocidin; tool; treatment response; validation studies; white matter; white matter damage

Chronic heavy or binge alcohol consumption damages the structural and functional integrity of the brain. Ethanol’s neurotoxic and degenerative effects target white matter (WM) across the lifespan, resulting in loss of myelin, impaired myelin maintenance, and degeneration of axons. Since WM integrity is critical to many CNS functions, better understanding of how ethanol exerts its adverse effects on WM is needed to prevent or remediate the associated neurobehavioral and cognitive deficits. Oligodendrocyte dysfunction is at the core of WM degeneration since oligodendroglia are responsible for synthesizing and maintaining myelin. Myelin is needed to support and protect axons and ensure efficient neuronal conductivity. We hypothesize that alcohol- related brain degeneration (ARBD) involving WM could be divided into: 1) an early, reversible stage that is mainly associated with myelin loss and mediated by oxidative stress, inflammation, and neurotoxic ceramide accumulation via myelin breakdown and dysregulation of lipid metabolism; and 2) a later stage marked by impaired insulin/IGF-1 signaling through PI3K-Akt-mTOR-mTORC. Consequences of the latter include loss of mature oligodendrocytes and compact myelin, impaired maturation of oligodendroglia, axonal damage, and further progressive dysregulated sphingolipid metabolism with ceramide accumulation and sulfatide depletion. We anticipate that abstinence will be sufficient to remediate early stages of WM ARBD, whereas active interventions, such as insulin sensitizer treatments, will be required to reverse WM damage sustained by long periods of heavy alcohol exposure. However, both early and late stages of ARBD will likely respond to ceramide inhibitors such as myriocin. Aim 1 will characterize the structural, biochemical and molecular pathologies of early-stage WM ARBD in an established rat model of chronic ethanol exposure. Aim 2 will utilize a rat model and human postmortem brains to assess the roles of impaired insulin/IGF-1 signaling through PI3K-Akt-mTOR and mTORC1 versus mTORC2 as drivers of oligodendrocyte dysfunction and altered sphingolipid metabolism in the later stages of WM ARBD. Aim 3 will evaluate the effectiveness of abstinence, ceramide inhibitor, and insulin sensitizer treatments in remediating oligodendrocyte dysfunction and associated alterations in myelin sphingolipid composition in early versus late stages of WM ARBD. In addition, a novel sub-aim will determine the degree to which ethanol-induced CNS WM myelin sphingolipid abnormalities and their responses to treatment can be detected in peripheral blood mononuclear cells (PBMCs). Our underlying hypotheses are addressed through the use of quantitative immunohistochemistry, electron microscopy, multiplex ELISAs, mRNA studies, and Matrix-assisted laser desorption/ionization-imaging mass spectrometry. The research plan is novel, mechanistic, robust, transparent, and inclusive of both sexes, human validation studies, prospects for stratifying treatment according to ARBD stage, and approaches for potentially monitoring ARBD-associated WM biochemical pathology and responses to treatment with non-invasive PBMC assays.

长期大量或酗酒会损害大脑的结构和功能完整性。 乙醇的神经毒性和退化作用会影响整个生命周期的白质 (WM)，导致白质损失 髓磷脂、髓磷脂维持受损和轴突退化，因为 WM 完整性对许多中枢神经系统至关重要。 功能，需要更好地了解乙醇如何对 WM 产生不利影响，以预防或 修复相关的神经行为和认知缺陷是少突胶质细胞功能障碍的核心。 由于少突胶质细胞负责合成和维持髓磷脂，因此 WM 变性。 需要支持和保护轴突并确保有效的神经传导性。 涉及 WM 的相关脑变性 (ARBD) 可分为： 1) 早期、可逆阶段，即 主要与髓磷脂损失有关，由氧化应激、炎症和神经毒性神经酰胺介导 通过髓磷脂分解和脂质代谢失调而积累；2）后期阶段 通过 PI3K-Akt-mTOR-mTORC 的胰岛素/IGF-1 信号传导受损，后者的后果包括丧失。 成熟的少突胶质细胞和致密髓磷脂，少突胶质细胞成熟受损，轴突损伤， 随着神经酰胺的积累和脑硫脂的消耗，鞘脂代谢进一步失调。 我们预计禁欲足以补救 WM ARBD 的早期阶段，而积极的 需要采取干预措施，例如胰岛素增敏剂治疗，以逆转长期持续的 WM 损害。 然而，ARBD 的早期和晚期都可能对神经酰胺有反应。 Aim 1 等抑制剂将表征其结构、生化和分子病理学。 在已建立的慢性乙醇暴露大鼠模型中进行早期 WM ARBD 目标 2 将利用大鼠模型。 和人类死后大脑，通过 PI3K-Akt-mTOR 评估受损的胰岛素/IGF-1 信号传导的作用 mTORC1 与 mTORC2 作为少突胶质细胞功能障碍和鞘脂代谢改变的驱动因素 在 WM ARBD 的后期阶段，目标 3 将评估禁欲、神经酰胺抑制剂和药物的有效性。 胰岛素增敏剂治疗可修复少突胶质细胞功能障碍和相关髓鞘质改变 WM ARBD 早期与晚期的鞘脂组成此外，还将确定一个新的子目标。 乙醇诱导的中枢神经系统 WM 髓磷脂鞘脂异常的程度及其对 治疗可以在外周血单核细胞（PBMC）中检测到。我们的基本假设是。 通过使用定量免疫组织化学、电子显微镜、多重 ELISA 来解决， mRNA 研究和基质辅助激光解吸/电离成像质谱研究计划。 是新颖的、机械的、稳健的、透明的、并且包容两性、人体验证研究、前景 根据 ARBD 阶段分层治疗，以及潜在监测 ARBD 相关的方法 WM 生化病理学和对非侵入性 PBMC 检测治疗的反应。