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PPARdelta receptors and alcohol use phenotypes

PPARδ 受体和饮酒表型

基本信息

批准号：
10682348
负责人：
ERIC P ZORRILLA
金额：
$ 21.49万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682348
关键词：
Addictive Behavior Address Affect Affinity Agonist Alcohol consumption Alcohol withdrawal syndrome Alcoholism American Medical Association Amygdaloid structure Anatomy Animal Model Anxiety Attention Behavior Behavior Disorders Bioenergetics Biology Blood - brain barrier anatomy Brain CD3D gene CNR1 gene Carrier Proteins Chemicals Chronic Corpus striatum structure Coupled Data Development Dose Drug Modelings Emotional Epigenetic Process Ethanol Ethanol Metabolism Exercise GTP-Binding Proteins Gene Expression Genes Genetic Genetic Recombination Genotype Homeostasis Human Intervention Knock-out Knockout Mice Knowledge Laboratory Study Lifestyle-related condition Ligand Binding Ligands Lipids Mediator Medical Membrane Metabolic Mitochondria Modeling Molecular Mus Neurobiology Nuclear Nuclear Receptors PPAR delta Pathway interactions Peripheral Peroxisome Proliferator-Activated Receptors Persons Phenotype Prefrontal Cortex Receptor Activation Receptor Inhibition Regulation Resistance Rewards Role Self Administration Signal Transduction Site Skeletal Muscle Specificity Stress Substance Use Disorder Testing Therapeutic Transgenic Organisms Translating Withdrawal addiction alcohol abuse therapy alcohol use disorder behavior measurement cell growth regulation cell type conditional knockout emotional behavior fatty acid-binding proteins insight mimetics multidisciplinary nerve stem cell nestin protein neuroinflammation novel pharmacologic pre-clinical preference receptor response therapeutic target tool transcription factor transcriptomics vapor

项目摘要

Abstract New neurobiological understanding of and therapeutic targets for alcohol use disorder (AUD) are needed. Advances in the biology of AUD indicate that lipid signaling is a key regulator of ethanol use and withdrawal behavior via specialized G-protein coupled membrane receptors, transport proteins, and, more recently, nuclear transcription factors. PPARs are lipid-sensing transcription factors encoded by 3 genes (PPAR, PPAR, PPAR) that were identified for their roles in peripheral regulation of fuel homeostasis. PPAR and PPAR have received intense attention for their anti-addiction-like actions. Yet, the central role of the more abundantly expressed brain PPARreceptor isotype in the control of compulsive alcohol use behaviors is entirely unknown. Here, we test the overarching hypothesis that brain peroxisome proliferator-activated receptors-delta subtype (PPAR) inhibits compulsive ethanol use and negative emotional withdrawal. Studies use the chronic intermittent ethanol vapor exposure model to elicit escalated and aversion-resistant ethanol intake and withdrawal anxiety- and irritability-like behavior to yield new translational insights into AUD. We combine novel brain-penetrant and translatable PPAR agonist (KD3010, T3D-959) and brain-restricted and site-specific cre/lox conditional PPAR knockouts to test the causal role and central sites of PPARaction in compulsive-like alcohol use phenotypes. The resulting data and novel genetic and translationally-relevant pharmacological tools for this understudied PPARδ isotype will lay the groundwork for cell type- and anatomically-specific mechanistic studies and may lead to interventions for people affected by compulsive alcohol use and other forms of addiction.

摘要需要对酒精使用障碍（AUD）的神经生物学理解和治疗靶点。 AUD生物学的进展表明，脂质信号是乙醇使用和戒断的关键调节因子行为通过专门的G蛋白偶联膜受体，转运蛋白，和，最近，核转录因子PPARs是由3个基因编码的脂质敏感转录因子（PPARs，过氧化物酶体增殖物激活物受体（PPARs），过氧化物酶体增殖物激活物受体（PPARs），其被鉴定为在燃料稳态的外周调节中的作用。过氧化物酶体增殖物受体由于其抗成瘾的作用，过氧化物酶体增殖物激活物受体（PPAR）已经受到了广泛的关注。然而，更重要的是，大脑中大量表达的过氧化物酶体增殖物激活体受体亚型在控制强迫性酒精使用行为中的作用，完全未知在这里，我们测试了大脑过氧化物酶体增殖物激活的总体假设，受体-δ亚型（PPAR-A）抑制强迫性酒精使用和消极情绪戒断。研究使用慢性间歇性乙醇蒸气暴露模型来引起乙醇的增加和厌恶摄入和戒断焦虑和易怒样行为，以产生对AUD的新的翻译见解。我们联合收割机将新的脑渗透和可翻译的PPAR γ激动剂（KD 3010，T3 D-959）和脑限制性和位点特异性cre/lox条件性PPARmRNA敲除，以测试PPARmRNA敲除作用的因果作用和中心位点，强迫性酒精使用表型由此产生的数据和新的遗传和预防相关的这种未充分研究的过氧化物酶体增殖物激活受体δ同种型的药理学工具将为细胞类型和解剖学特定的机制研究，并可能导致受强迫症影响的人的干预措施酒精使用和其他形式的成瘾。