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

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

慢性大量或暴饮暴食的饮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效应靶向白质（WM），导致失去髓磷脂，髓鞘维护受损和轴突变性。由于WM的完整性对许多CNS至关重要功能，更好地理解乙醇如何对WM施加不利影响，以防止或补救相关的神经行为和认知缺陷。少突胶质细胞功能障碍是 WM变性以来，少突胶质细胞负责合成和维持髓磷脂。髓鞘是需要支持和保护轴突并确保有效的神经元电导率。我们假设酒精 - 涉及WM的相关大脑变性（ARBD）可以分为：1）早期，可逆阶段主要与髓磷脂损失相关，并由氧化应激，感染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积累； 2）以后的阶段通过PI3K-AKT-MTOR-MTORC受损的胰岛素/IGF-1信号传导。后者的后果包括丢失成熟的少突胶质细胞和紧凑的髓磷脂，少突胶质细胞的成熟，轴突损伤和进一步的渐进性失调，鞘脂代谢，神经酰胺积累和硫化物耗竭。我们预计禁欲将足以补充WM ARBD的早期阶段，而活跃干预措施（例如胰岛素敏感性治疗）将需要逆转长期造成的WM伤害大量酒精暴露时期。但是，ARBD的早期和晚期都可能对神经酰胺作出反应抑制剂，例如霉菌素。 AIM 1将表征结构，生化和分子病理的在已建立的慢性乙醇暴露大鼠模型中的早期WM ARBD。 AIM 2将利用大鼠模型和人类后大脑，以评估通过PI3K-AKT-MTOR的胰岛素/IGF-1信号受损的作用 MTORC1与MTORC2作为少突胶质功能障碍的驱动因素并改变了鞘脂代谢在WM ARBD的后期。 AIM 3将评估禁欲，神经酰胺抑制剂和胰岛素敏感性治疗方法在修复少突胶质功能障碍和髓磷脂的相关改变中 WM ARBD的早期与晚期的鞘脂组成。此外，新颖的子艾姆将确定乙醇引起的CNS WM髓鞘鞘脂异常的程度及其对可以在外周血单核细胞（PBMC）中检测到治疗。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ELISAS来解决 mRNA研究，以及基质辅助激光解吸/电离成像质谱法。研究计划是新颖的，机械的，健壮的，透明的，并且包括性别，人类验证研究，前景根据ARBD阶段对处理进行分层，并可能监测ARBD相关的方法 WM生化病理学和对非侵入性PBMC测定法治疗的反应。