Endocrine Regulation of Alcohol Intake

酒精摄入的内分泌调节

• 批准号: 9887298
• 负责人: Matthew Joseph Potthoff
• 金额: $ 45.08万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887298
• 关键词: Acute; Address; Adolescent and Young Adult; Adult; Affect; Alcohol consumption; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Animal Model; Automobile Driving; Behavior; Behavioral; Biological Assay; Brain; Cardiovascular Diseases; Cells; Chronic; Consummatory Behavior; Consumption; Data; Diagnosis; Dissection; Dopamine; Drug usage; Economic Burden; Endocrine; Enterobacteria phage P1 Cre recombinase; Ethanol; Etiology; Feedback; Genes; Genetic Polymorphism; Genetic Variation; Glutamates; Goals; Grant; Health Care Costs; Healthcare; Heavy Drinking; Hormonal; Hormones; Human; Individual; Knock-out; Knockout Mice; Liver; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolic syndrome; Metabolism; Modeling; Mus; National Institute on Alcohol Abuse and Alcoholism; Neuraxis; Neurons; Nucleus Accumbens; Pathologic; Pathway interactions; Peripheral; Pharmacologic Substance; Pharmacology; Physiological; Physiology; Population; Prevalence; Production; Regulation; Rewards; Role; Series; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Synaptic Transmission; System; Techniques; Testing; Therapeutic; Time; Tissues; United States; Ventral Tegmental Area; Work; alcohol abuse therapy; alcohol exposure; alcohol use disorder; base; binge drinking; cancer risk; designer receptors exclusively activated by designer drugs; fibroblast growth factor 21; genomic locus; improved; in vivo; innovation; insight; mesolimbic system; mouse model; neural circuit; new therapeutic target; novel; preference; prevent; productivity loss; promoter; receptor; targeted treatment; therapeutic target; tool

PROJECT SUMMARY / ABSTRACT In the United States, alcohol use disorder (AUD) affects ~15% of adults with the prevalence of binge drinking on the rise in adolescents and young adults. AUD represents a major issue to healthcare given that chronic excessive alcohol consumption in humans is associated with cardiovascular disease, metabolic syndrome, and cancer while acute alcohol intoxication can prove lethal. Economically, AUD represents a massive burden due to loss of productivity and associated healthcare costs. Recently, the endocrine hormone fibroblast growth factor 21 (FGF21), known for its potent metabolic effects, was found to significantly reduce alcohol consumption via signaling through its obligate co-receptor, β-klotho, in the brain. Importantly, single nucleotide polymorphisms (SNPs) in both the FGF21 and β-klotho genomic loci are highly associated with increased alcohol consumption in humans. Our preliminary data demonstrates that FGF21 treatment markedly suppresses alcohol consumption in mice previous subjected to chronic alcohol exposure. Furthermore, excessive alcohol consumption promotes FGF21 secretion from the liver representing a homeostatic feedback loop to regulate alcohol consumption. However, the mechanism of FGF21 action in the brain and the neuronal target(s) for these effects has not been determined. The overall goal of this proposal is to identify the neural circuit(s) regulating FGF21-mediated suppression of alcohol intake. The aims of this grant are to 1) determine the direct neuronal target(s) of FGF21 in the CNS mediating inhibition of alcohol intake, and 2) determine how FGF21 modulates reward circuits to regulate alcohol intake and preference. To accomplish these aims, we have generated novel animal models and tools to examine these experimental aims. These studies will provide new fundamental insights into the regulation of alcohol intake by peripheral endocrine signals acting on the central nervous system. In addition, these studies may identify novel therapeutic targets for the treatment of AUD.

项目摘要 /摘要 在美国，酒精使用障碍（AUD）影响了大约15％的成年人 青少年和年轻人的兴起。 AUD代表了医疗保健的主要问题 人类过量的饮酒与心血管疾病，代谢综合征和 癌症而急性酒精中毒可以证明是致命的。从经济上来说，AUD代表了巨大的烧伤 损失生产率和相关的医疗费用。最近，内分泌辣椒成纤维细胞生长 因素21（FGF21）以其潜在的代谢作用而闻名，可显着降低酒精 通过其强制性共受体β-Klotho在大脑中通过信号传导消耗。重要的是，单核苷酸 FGF21和β-Klotho基因组局部的多态性（SNP）都与增加 人类饮酒。我们的初步数据表明，FGF21治疗明显 抑制先前受到慢性酒精暴露的小鼠的饮酒。此外， 过度饮酒会促进代表稳态反馈的肝脏的FGF21分泌 循环调节饮酒。但是，FGF21在大脑和神经元中作用的机制 这些影响的目标尚未确定。该提议的总体目标是确定中立 对FGF21介导的酒精摄入抑制的电路。这笔赠款的目的是1）确定 FGF21的直接神经元靶标在中枢神经系统中介导的酒精摄入抑制和2）确定如何确定 FGF21调节奖励电路以调节酒精摄入和偏好。为了实现这些目标，我们 已经生成了新型的动物模型和工具来检查这些实验目标。这些研究将提供 对外周内分泌信号对酒精摄入的调节的新基本见解，作用于 中枢神经系统。此外，这些研究可能确定用于治疗的新型治疗靶标 奥德