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

项目摘要 在黑暗中高饮酒(HDID)的小鼠已经被选择性地培育成醉酒。HDID小鼠是 在基因上截然不同，并代表了药物筛选的独特基因。许多能还原的化合物 其他品系(如C57BL/6J)的饮酒并不能减少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，酒精改变了炎症信号。我们 使用了一种严格的方法来测试几种针对免疫信号的化合物是否可以 减少HDID小鼠的暴饮式饮酒。到目前为止，在HDID小鼠身上测试的28种化合物中有14种能够 减少HDID小鼠的暴饮式饮酒。阿普米司特，一种磷酸二酯酶4型抑制剂，我们最 有希望的临床靶点，以及其他减少酗酒的化合物有一个共同点-- 它们增加了抗炎(如IL-10)信号。这些结果提供了一个大致统一的假说 更机械的实验来研究促炎和抗炎信号的平衡是如何调节的 HDID小鼠暴饮暴食。在这里，我们在类似狂欢的启动的背景下研究这一机制 并确定这一框架在长期酗酒条件下是否适用。一个 这项提案的首要目标是确定和瞄准抗炎签名，以减少饮酒和 恢复酒精引起的大脑中抗炎和促炎信号的变化。特定的AIM 1测试 特定的炎症信号通路是否有助于iHDID小鼠使用 互补的分子、遗传、药理学和行为方法的结合 与INIA-N PI罗伯托、曼吉里、比尔博和拉塞克合作。特定目标2测试慢性狂欢是否- 在iHDID-1小鼠中，与饮酒一样，抗炎基因的表达伴随和/或调节着抗炎基因的表达。目标2将 利用信息学方法识别化合物，以进行行为和分子研究 与INIA-N Pi Mayfield一起。该项目还与INIA-Stress PI Vazey/Mooreman和 Becker/Lopez测试有希望的化合物对其他行为的影响，并分享了HDID和HS/NPT 与全国的研究人员一起，将老鼠品系作为独特的资源在该奖项下开发和维护。

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.