Alcohol-induced epigenetic reprogramming of PPAR-α affects allopregnanolone biosynthesis

酒精诱导的 PPAR-α 表观遗传重编程影响异孕酮生物合成

• 批准号: 10658534
• 负责人: GRAZIANO PINNA
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658534
• 关键词: Acute; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Allopregnanolone; Amygdaloid structure; Anabolism; Anti-Anxiety Agents; Anxiety; Area; Autopsy; Basic Science; Biological Assay; Brain; Cause of Death; Cerebellum; Cholesterol; Chromatin Remodeling Factor; Chronic; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; Dorsal; Down-Regulation; Enzymes; Epigenetic Process; Estrous Cycle; Ethanol; Ethanol dependence; FDA approved; Female; Fenofibrate; Gene Expression; Genes; Hippocampus; Human; Hydroxysteroid Dehydrogenases; Impairment; Isomerism; Link; Mass Fragmentography; Measures; Medial; Methods; Methyl-CpG-Binding Protein 2; Methylation; Mixed Function Oxygenases; Modeling; Modification; Molecular; Mood Disorders; Neurobiology; Neurons; Nuclear Receptors; Nucleus Accumbens; Oxidoreductase; PPAR alpha; Pathway interactions; Peroxisome Proliferators; Phenotype; Prefrontal Cortex; Pregnanolone; Pregnenolone; Progesterone; Proteins; Publishing; Rattus; Regulation; Rodent; Rodent Model; Signal Transduction; Stress; Symptoms; Withdrawal; Withdrawal Symptom; alcohol effect; alcohol exposure; alcohol reward; alcohol use disorder; antagonist; anxiety-like behavior; anxious behavior; biological adaptation to stress; chromatin immunoprecipitation; comorbidity; demethylation; emotional behavior; epigenetic regulation; improved; mRNA Expression; male; neural; neuropsychiatric disorder; neurosteroids; palmidrol; pharmacologic; protein expression; receptor; transcription factor; transcriptomics; translational impact; translational model; vapor

Abstract. The neural substrates underlying alcohol use disorder (AUD), remain poorly understood in part due to lack of translational models that recapitulate phenotypes from the human condition. Biosynthesis of the GABAergic neurosteroid, allopregnanolone (Allo) in corticolimbic neurons, regulates stress sensitivity and induces a potent anxiolytic action. In a rodent model of chronic intermittent ethanol (CIE) exposure, decreased expression of Allo biosynthetic enzymes, 5α-reductase type I (5α-RI) and 3α-hydroxy-steroid dehydrogenase (3α-HSD) is associated with Allo level downregulation in the hippocampus (HIP) and cerebellum. Consistently, in AUD postmortem brain, cerebellum Allo levels and neurosteroidogenic proteins and enzymes, such as the translocator protein (TSPO), 5α-RI and 3α-HSD expression decreased in association with aberrant epigenetic marks. Alcohol-induced epigenetic modifications (e.g., DNA hyper/hypomethylation) on transcriptomics and their impact on neurosteroidogenic gene expression, neurosteroid levels, and anxiety are poorly understood. Allo biosynthesis can be upregulated in brain areas that modulate anxiety and alcohol reward by stimulating the epigenetically modifiable nuclear receptor, peroxisome proliferator-regulated receptor (PPAR)-α by the endogenous modulator, palmitoylethanolamide (PEA). Intriguingly, chronic alcohol exposure decreases PPAR- α expression, while stimulation of PPAR-α by PEA decreases both anxiety and alcohol intake. The molecular mechanisms underlying these effects remain unclear. Our preliminary and published results suggest that alcohol-induced aberrant regulation of PPAR-α may affect anxiety via decreasing Allo content. Hypothesis: Chronic alcohol exposure alters methylation/demethylation dynamics that downregulate corticolimbic PPAR-α expression and allopregnanolone biosynthesis, and elevated anxiety. In male and female rats, we will: (AIM 1) Examine the effect of 14-day CIE exposure (EtOH), ethanol acute (24h, W24h) and protracted (7 days, W7d) withdrawal on the epigenetic regulation of PPAR-α expression and downstream effects on neurosteroidogenic enzyme expression; (AIM 2) Investigate the effects of CIE exposure and ethanol acute and protracted withdrawal on the brain content of Allo; and (AIM 3) Study the pharmacoepigenetics of PEA and fenofibrate on Allo biosynthesis and anxiety after CIE exposure and acute and protracted ethanol withdrawal. This study may unveil CIE-induced neurobiological alterations and suggest treatment targets for alcohol withdrawal symptoms.

抽象的。酒精使用障碍（AUD）的神经底物（AUD）在某些部分归功于 缺乏翻译模型，这些模型会从人类条件中概括表型。生物合成 GABA能神经类固醇，皮质胶质神经元中的异烷醇酮（Allo），调节胁迫敏感性和 诱导潜在的抗焦虑作用。在慢性间歇性乙醇（CIE）暴露的啮齿动物模型中， Allo Biosynthetic酶的表达，5α-还原酶I型（5α-RI）和3α-羟基类固醇脱氢酶的表达 （3α-HSD）与海马（髋关节）和小脑中的Allo水平下调有关。一贯 在AUD术后大脑中 易位蛋白（TSPO），5α-RI和3α-HSD表达与异常表观相关 标记。酒精诱导的表观遗传学修饰（例如，DNA高/甲基化）在转录组学上和 它们对神经类固醇基因表达，神经固醇水平和焦虑的影响很少。 可以通过刺激来调节动画和酒精奖励的大脑区域进行Allo Biosynsiss进行更新 表观遗传修饰的核受体，过氧化物体增生剂调节的受体（PPAR）-α由 内源调节剂，棕榈乙醇酰胺（PEA）。有趣的是，慢性酒精暴露降低了PPAR- α表达，而通过PEA刺激PPAR-α会降低焦虑和酒精摄入量。分子 这些效果的基础机制尚不清楚。我们的初步和发表的结果表明 酒精诱导的PPAR-α的异常调节可能会通过减少Allo含量来影响焦虑。假设： 慢性酒精暴露会改变甲基化/脱甲基化动力学，从而下调皮质Lbic PPAR-α 表达和异源性生物合成和动画升高。在男性和雌性老鼠中，我们将：（目标1） 检查14天CIE暴露（ETOH），乙醇急性（24H，W24H）和长期的影响（7天，W7D） 对PPAR-α表达的表观遗传调节和对神经固醇激发的影响 酶表达； （AIM 2）研究CIE暴露和乙醇急性和持久的影响 提取Allo的大脑含量； （AIM 3）研究PEA的药物外皮材料和fenobitrate CIE暴露后的Allo生物合成和动画以及急性和持久的乙醇戒断。这项研究可能 揭示了CIE引起的神经生物学改变，并提出了戒酒症状的治疗目标。