Gene Network Perturbations in Alcohol Dependence - A Systems BiologyApproach

这是第一次有竞争力的更新一个创新项目的界面计算 分析基因网络调控和行为药理学，旨在识别和探索 关于过度饮酒进展的新的可检验的机制和治疗假设， 酒精依赖，弹性和发展酒精使用障碍（AUD）的脆弱性。的 最终目标是揭示和验证新的和更有效的治疗AUD的靶点。 当前（第一个）资助期的结果表明， 表型显著性可以用目前的实验-计算系统来鉴定 生物学战略;这有助于确定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，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一个更高的分辨率水平，使承担基因 通过荧光纯化的神经元、星形胶质细胞、小胶质细胞和少突胶质细胞的表达谱， 活化细胞分选（FACS）从具有中度或中度脑损伤史的大鼠的关键脑区域中进行。 过度（升级）酒精自我管理。在此测试下的子假设 方法是在细胞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异性和常见基因网络失调，并可能指向以前 治疗潜力的未被认识的调节机制。具体目标2将测试子目标 主调节基因（MR）控制特定基因表达的假说 与酒精效应相关的信号在酒精动机中具有特定的作用， 作为候选药物靶点。特别是，具体目标2中的研究将探讨选定的 从目前资助的基因调控分析中得出的机制假设 根据拟议的具体目标1，它们在过量酒精表型中的作用 使用计算、生物化学、行为和形态学策略来饮酒。 总之，本提案将探索细胞中的转录网络失调- 类型水平的分析与适度和过量的酒精摄入量，以确定新的 关于过度饮酒的神经生物学基础的机械假说， 以识别AUD的新治疗靶点。

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.