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Coordinate Regulation of an Alcohol Protective Response by the Liver-derived Hormone FGF21

肝源性激素 FGF21 协调调节酒精保护反应

基本信息

批准号：
10029530
负责人：
STEVEN A. KLIEWER
金额：
$ 36.78万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10029530
关键词：
Adipose tissue Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcoholic liver damage Alcohols Automobile Driving Body Temperature Brain Brown Fat Clinical Trials Collection Consumption Disease Dose Estrogen receptor positive Ethanol FGF21 gene Fructose Genetic Transcription Genetically Engineered Mouse Hormones Human Hydration status Knock-out Knockout Mice Life Link Liver Mediating Metabolic Diseases Mitochondria Modeling Mus Nerve Nervous system structure Neuraxis Neurons Neuropeptides Neurotensin Nonesterified Fatty Acids Pathology Pathway interactions Pharmacologic Substance Pharmacology Play Regulation Rodent Role Series Stimulus Stress Sympathetic Nervous System Testing Thermogenesis Tissues Toxic effect Water Water consumption alcohol effect alcohol exposure alcohol response drinking water experimental study fatty acid oxidation genome wide association study health economics hepatoma cell induced hypothermia insight knock-down liver injury natural hypothermia novel therapeutic intervention preference prevent protective effect receptor response sugar transcription factor uncoupling protein 1

项目摘要

Project Summary Alcohol abuse and related diseases exact a staggering health and economic toll, and thus there is a dire need for novel therapeutic approaches. The hormone FGF21, which is rapidly and robustly induced in liver in response to ethanol exposure, is an exciting new pharmaceutical candidate. FGF21 acts on the brain to suppress alcohol consumption and to stimulate water drinking. In this application, we propose that FGF21 mediates these protective effects by acting directly on neurons expressing the neuropeptide, neurotensin, which is a well-established regulator of ethanol and water intake. We further propose that liver-derived FGF21 also protects against ethanol-induced hypothermia and liver injury by activating the sympathetic nervous system and stimulating thermogenesis in brown adipose tissue. We will test these hypotheses in a series of experiments that employ our unique collection of genetically-engineered mouse models, including mice selectively lacking FGF21’s obligate co-receptor -Klotho in neurotensin neurons. We anticipate that these studies will provide important insights into the tissues and underlying mechanisms whereby FGF21 protects against ethanol-induced toxicity. Moreover, since FGF21 is already in clinical trials for metabolic disease-related indications, these studies will aid in determining whether FGF21 can be repurposed pharmaceutically for treating alcohol abuse and its associated pathologies.

项目总结