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

项目摘要 酗酒和相关疾病造成了惊人的健康和经济损失，因此， 需要新的治疗方法。在肝脏中快速且强烈诱导的激素FGF 21 是一种令人兴奋的新药物候选者。FGF 21作用于大脑， 抑制酒精消耗和刺激饮水。在本申请中，我们提出FGF 21 通过直接作用于表达神经肽，神经降压素， 这是一种公认的乙醇和水摄入量调节剂。我们进一步提出，肝源性 FGF 21还通过激活交感神经系统保护乙醇诱导的低体温和肝损伤。 神经系统和刺激棕色脂肪组织产热。我们将在一个 一系列实验采用我们独特的基因工程小鼠模型，包括 在神经降压素神经元中选择性缺乏FGF 21的专性共受体α-Klotho的小鼠。我们预计 这些研究将提供重要的见解，组织和潜在的机制， 防止乙醇引起的毒性。此外，由于FGF 21已经在代谢的临床试验中， 疾病相关的适应症，这些研究将有助于确定FGF 21是否可以重新利用 用于治疗酒精滥用及其相关病理的药物。

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.