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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