8/11 Targeting Anti-inflammatory Gene Expression in Binge-like Drinking

项目摘要 在黑暗中大量饮酒（HDID）的小鼠被选择性地培育为醉酒。HDID小鼠 在遗传上不同，并代表用于药物筛选的独特基因型。许多化合物， 饮用其他菌株（例如，C57 BL/6 J）不能减少HDID小鼠的饮酒，也不能减少饮酒 在人类身上。许多INIA神经免疫研究发现酒精会改变炎症信号。我们 采用严格的方法来测试几种靶向免疫信号的化合物是否可以 减少HDID小鼠的暴饮暴食。迄今为止，在HDID小鼠中测试的28种化合物中有14种能够 减少HDID小鼠的暴饮暴食。阿普斯特，一种磷酸二酯酶4型抑制剂， 有前途的临床目标，和其他化合物，减少暴饮暴食有一个共同点- 它们增加抗炎（例如IL-10）信号传导。这些结果提供了一个广泛统一的假设， 更多的机械实验来研究促炎和抗炎信号的平衡如何调节 HDID小鼠的暴饮暴食。在这里，我们研究这种机制的背景下，启动暴食样 饮酒，并确定这一框架是否适用于慢性酗酒条件下。一个 该提案的总体目标是确定和靶向抗炎信号，以减少饮酒， 恢复酒精引起的大脑中抗炎和促炎信号的变化。特定目标1测试 是否特定的炎症信号通路有助于iHDID小鼠的暴食样饮酒， 互补的分子，遗传，药理学和行为方法的组合， 与INIA-N PI Roberto、Mangieri、Bilbo和Lasek合作。具体目标2测试是否慢性暴食- 在iHDID-1小鼠中，饮酒伴随和/或受到抗炎基因表达的调节。目标2将 采用信息学方法来识别化合物，用于合作进行行为和分子研究 INIA-N PI梅菲尔德该项目还与INIA压力PI Vazey/Mooreman合作， Becker/洛佩斯来测试有前途的化合物对其他行为的影响，并分享了HDID和HS/NPT 鼠标线作为独特的资源开发和维护根据这一奖项与全国各地的调查人员。

Project Summary High Drinking in the Dark (HDID) mice have been selectively bred to drink to intoxication. HDID mice are genetically distinct and represent a unique genotype for drug screening. Many of the compounds that reduce drinking in other strains (e.g., C57BL/6J) do not reduce drinking in HDID mice, and also fail to reduce drinking in humans. Many INIA-Neuroimmune studies have found that alcohol alters inflammatory signaling. We employed a rigorous approach for testing whether several compounds targeting immune signaling could reduce binge-like drinking in HDID mice. To date, 14 out of 28 compounds tested in HDID mice were able to reduce binge-like drinking in HDID mice. Apremilast, a phosphodiesterase type 4 inhibitor and our most promising clinical target, and other compounds that reduced binge-like drinking have one thing in common - they increase anti-inflammatory (e.g. IL-10) signaling. These results offer a broadly unifying hypothesis for more mechanistic experiments to investigate how the balance of pro- and anti-inflammatory signaling regulates binge-like drinking in HDID mice. Here, we study this mechanism in the context of initiation of binge-like drinking, and determine whether this framework holds true under chronic binge drinking conditions. An overarching goal of this proposal is to identify and target anti-inflammatory signatures to reduce drinking and restore alcohol-induced changes in anti- and pro-inflammatory signaling in the brain. Specfic Aim 1 tests whether specific inflammatory signaling pathways contribute to binge-like drinking in iHDID mice using a combination of complementary molecular, genetic, pharmacological, and behavioral approaches in collaboration with INIA-N PIs Roberto, Mangieri, Bilbo, and Lasek. Specific Aim 2 tests whether chronic binge- like drinking is accompanied and/or regulated by anti-inflammatory gene expression in iHDID-1 mice. Aim 2 will employ informatics approaches to identify compounds for behavioral and molecular studies in collaboration with INIA-N PI Mayfield. This project also collaborates with INIA-Stress PIs Vazey/Mooreman and Becker/Lopez to test the effects of promising compounds on other behaviors, and shares the HDID and HS/Npt mouse lines as unique resources developed and maintained under this award with investigators nationwide.