Gene Network Perturbations in Alcohol Dependence - A Systems BiologyApproach

这是第一次在计算界面上对创新项目进行竞争性更新 旨在识别和探索的基因网络调控和行为药理学分析 新的可测试的机制和治疗假说进展为过度饮酒和 酒精依赖、恢复力和易患酒精使用障碍(AUD)。这个 最终目标是揭示和验证AUD的新的和更有效的治疗靶点。 当前(第一个)资助期的结果表明，酒精行动的广泛监管机构 表型意义可以用目前的实验-计算系统来识别 生物学策略；有助于确定用于重新定位的3种候选药物 目前正在进行临床试验的AUD。在这些成果的基础上，在具体目标1 在拟议的第二个资助期，我们的目标是了解相互作用的分子基础 酒精与基因调控网络在更高水平上的分辨率通过带来基因 荧光法纯化的神经元、星形胶质细胞、小胶质细胞和少突胶质细胞的表达谱 中度或中度以上病史大鼠关键脑区的激活细胞分类(FACS) 过度(升级)的酒精自我管理。用这个进行检验的子假说 方法是在细胞分辨率水平上进行基因调控分析将使我们能够 确定关键细胞类型特定的和常见的基因网络失调，并可能指向先前 治疗潜力的调节机制未知。《特定目标2》将试探子- 假设控制特定基因表达的主要调节基因(MRS) 与酒精影响相关的信号在酒精的动机中具有特定的作用，并且可以 作为候选的可下药目标。特别是，在特定目标2中的研究将探索选定的 机制假说源自目前基金中进行的基因调控分析 期间和拟议的具体目标1，说明它们在过量饮酒表型中的作用 使用计算、生化、行为和形态策略饮酒。 综上所述，本提案将探讨细胞转录网络失调-- 键入与适度和过量酒精摄入量相关的分析水平，以确定新的 关于过度饮酒神经生物学基础的机械论假说 目的：寻找治疗AUD的新靶点。

This is the first competitive renewal of an innovative project at the interface of computational analysis of gene network regulation and behavioral pharmacology aimed at identifying and exploring new testable mechanistic and therapeutic hypotheses on the progression to excessive drinking and alcohol dependence, resilience and vulnerability to developing alcohol use disorder (AUD). The ultimate goal is to reveal and validate new and more effective therapeutic targets for AUD. Results of the current (first) funding period demonstrate that broad regulators of alcohol actions of phenotypic significance can be identified with the present experimental-computational systems biology strategies; which contributed to the identification of 3 candidate drugs for repositioning for AUD that are currently advancing toward clinical testing. Building on these results, in Specific Aim 1 of the proposed second funding period we aim to understand the molecular bases of the interactions of alcohol with the gene regulatory networks at a greater level of resolution by bringing to bear gene expression profiling of neurons, astrocytes, microglia and oligodendrocytes purified by fluorescence- activated cell sorting (FACS) from key brain regions of rats with histories of either moderate or excessive (escalated) alcohol self-administration. The sub-hypothesis under testing with this approach is that conducting gene regulation analyses at the cellular level of resolution will allow us to identify key cell type-specific and -common gene network dysregulations, and may point to previously unrecognized regulatory mechanisms of therapeutic potential. Specific Aim 2 will test the sub- hypothesis that the master regulator genes (MRs) governing the expression of specific gene signatures associated with the effects of alcohol have specific roles in motivation for alcohol and can serve as candidate druggable targets. In particular, studies in Specific Aim 2 will explore selected mechanistic hypotheses derived from gene regulatory analyses conducted in the current funding period and under the proposed Specific Aim 1 for their role in phenotypes of excessive alcohol drinking using computational, biochemical, behavioral and morphological strategies. Altogether, the present proposal will explore the transcriptional network dysregulations at the cell- type level of analysis associated with moderate and excessive alcohol intake to identify new mechanistic hypotheses on the neurobiological bases of excessive alcohol drinking that are expected to lead to the identification of novel therapeutic targets for AUD.