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惊人的健康和经济损失，因此有可怕的 需要新的治疗方法。在肝脏中迅速而有力地诱导的激素FGF21 作为对乙醇暴露的回应，是一种令人兴奋的新候选药物。FGF21作用于大脑以 抑制饮酒，刺激饮水。在本申请中，我们建议FGF21 通过直接作用于表达神经肽的神经元，神经降压素， 这是一个公认的乙醇和水摄入量的调节器。我们进一步提出，肝脏来源的 FGF21还通过激活交感神经保护乙醇引起的体温过低和肝损伤。 神经系统和刺激棕色脂肪组织的产热作用。我们将在一个 使用我们独特的基因工程小鼠模型的一系列实验，包括 选择性缺失成纤维细胞生长因子21‘的小鼠，S在神经降压素神经元上专有共受体-Klotho。我们预料到 这些研究将为FGF21的组织和潜在机制提供重要的见解 防止乙醇引起的毒性。此外，由于FGF21已经在代谢的临床试验中 与疾病相关的适应症，这些研究将有助于确定FGF21是否可以改变用途 用于治疗酒精滥用及其相关病理的药学研究。

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.