Involvement of Fibroblast Growth Factor-2 in alcohol use disorder

成纤维细胞生长因子 2 与酒精使用障碍的关系

• 批准号: 430949881
• 负责人: Professorin Dr. Claudia Grothe
• 金额: --
• 依托单位: Institut für Neuroanatomie und Zellbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/430949881?language=en
• 关键词: Involvement; Fibroblast; Growth; Factor; alcohol

The working hypothesis of the proposal is that excessive alcohol exposure induces fibroblast growth factor 2 (FGF2)-dependent neuroadaptations in the nigrostriatal system, leading to abnormal function of the dopaminergic system, and to the development of a compulsive, out-of-control drinking and alcohol addiction phenotypes. The general objective of the proposed project is to elucidate the mechanisms, by which FGF2 interacts with alcohol-drinking behaviors, i.e. alcohol regulates FGF2 expression, and FGF2 regulates alcohol-drinking behaviors. We will gain better understanding on a) which of the different FGF2 isoforms and b) how they affect the midbrain-striatum dopaminergic pathways that control behaviors related to addiction, as well as the effects of alcohol exposure on this system. In particular, we will treat four objectives to characterize the interaction of the different players in the addiction-related scenario with regard to biochemical, molecular, morphological, and behavioral parameters, i.e. the FGF2 system, the dopaminergic system, and other FGF2-related alcohol consumption genes in the nigrostriatal system. First, we aim to determine the isoforms, cellular source and localization of FGF2 and its target cells during alcohol consumption. Second, we plan to analyze the FGF2-related gene expression in the midbrain-striatal system driven by alcohol consumption. Third, long-lasting morphological changes in dopaminergic neurons related to the FGF2 increase will be elucidated. Finally, we will test whether suppression of the FGF2 system prevents these neuroadaptations and reduces alcohol consumption and relapse, as a potential pharmacotherapeutic strategy to treat alcohol use disorder.

该提案的工作假设是，过量的酒精暴露诱导黑质纹状体系统中的成纤维细胞生长因子2（FGF 2）依赖性神经适应，导致多巴胺能系统功能异常，并发展为强迫性、失控的饮酒和酒精成瘾表型。该项目的总体目标是阐明FGF 2与饮酒行为相互作用的机制，即酒精调节FGF 2表达，FGF 2调节饮酒行为。我们将更好地了解a）哪些不同的FGF 2亚型和B）它们如何影响控制成瘾相关行为的中脑-纹状体多巴胺能通路，以及酒精暴露对该系统的影响。特别是，我们将处理四个目标，以表征不同的球员在成瘾相关的情况下的生物化学，分子，形态学和行为参数，即FGF 2系统，多巴胺能系统，和其他FGF 2相关的酒精消费基因在黑质纹状体系统的相互作用。首先，我们的目标是确定在饮酒过程中FGF 2及其靶细胞的亚型，细胞来源和定位。其次，我们计划分析酒精消耗驱动的中脑-纹状体系统中FGF 2相关基因的表达。第三，将阐明与FGF 2增加相关的多巴胺能神经元的长期形态变化。最后，我们将测试抑制FGF 2系统是否可以防止这些神经适应，并减少饮酒和复发，作为治疗酒精使用障碍的潜在药物策略。