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）的神经基础仍然知之甚少，部分原因是 缺乏能够概括人类状况表型的翻译模型。生物合成 GABA能神经类固醇，皮质边缘神经元中的别孕烯醇酮（Allo），调节应激敏感性， 诱导有效的抗焦虑作用。在慢性间歇性乙醇（CIE）暴露的啮齿动物模型中， 异源生物合成酶，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（HIP）和小脑中的Allo水平下调相关。我们一贯认为， 在AUD死后的大脑，小脑Allo水平和神经类固醇生成蛋白和酶，如 TSPO、5α-RI和3α-HSD表达降低，与表观遗传异常相关。 标记.酒精诱导的表观遗传修饰（例如，DNA高/低甲基化）对转录组学的影响， 它们对神经类固醇基因表达、神经类固醇水平和焦虑的影响知之甚少。 Allo生物合成可以在通过刺激来调节焦虑和酒精奖励的大脑区域中上调 表观遗传修饰的核受体，过氧化物酶体增殖物调节受体（PPAR）-α， 内源性调节剂棕榈酰乙醇胺（PEA）。有趣的是，长期饮酒会降低PPAR- α的表达，而通过PEA刺激PPAR-α降低焦虑和酒精摄入量。分子 这些影响的潜在机制仍不清楚。我们的初步和发表的结果表明， 酒精诱导的PPAR-α的异常调节可能通过降低Allo含量而影响焦虑。假设： 慢性酒精暴露改变甲基化/去甲基化动力学，下调皮质边缘的PPAR-α 表达和别孕烯醇酮生物合成，以及焦虑升高。在雄性和雌性大鼠中，我们将：（AIM 1） 检查14天CIE暴露（EtOH）、乙醇急性（24 h，W24 h）和长期（7天，W7 d）的影响 停药对PPAR-α表达的表观遗传调节和神经类固醇生成的下游影响 目的2.研究CIE暴露和乙醇急性和长期暴露对大鼠肝细胞的影响 停药对Allo脑内容物的影响;（目的3）研究PEA和非诺贝特对大鼠脑内 CIE暴露和急性和长期乙醇戒断后的异源生物合成和焦虑。这项研究可能 揭示CIE诱导的神经生物学改变，并提出酒精戒断症状的治疗目标。