Of Mice and Primates: Gene Networks in Excessive Ethanol Consumption and Anxiety

描述（由申请人提供）：INIA-Stress联合体的一个基本前提是，至少在一定程度上，向滥用乙醇消费的进展是伴随并可能由生物体对压力反应的改变引起的，包括过量乙醇摄入/戒断的压力。我们认为，大脑基因表达网络的变化是导致进行性乙醇消耗和应激异常反应的适应机制的重要组成部分。我们之前在BXD重组自交系小组的大脑区域中使用了遗传和基因组方法来定义由急性乙醇调节的强大基因网络，并将这些基因网络与乙醇行为联系起来，特别是与应激反应有关。我们还发现了小鼠对急性乙醇的表达反应的显著重叠，以及由nia - stress联盟的PI Grant博士开发的过量乙醇摄入（SIP）灵长类动物模型中基因表达模式的改变。此外，最近在BXD小鼠中进行的多次慢性间歇性乙醇蒸汽（CIE）过度乙醇消耗模型的先导阵列研究发现，急性乙醇暴露的结果与我们从食食猴身上获得的数据具有显著的同源性。这些研究已经产生了基因网络，允许测试初始主要“枢纽”基因，以确定它们在调节乙醇消耗和CIE模型中对压力的反应中的可能作用。例如，我们最近通过AAV病毒载体基因传递研究发现，Gsk3p是乙醇消耗和戒断性焦虑的重要调节因子。基于这些发现，我们提出了以下组织假说：小鼠CIE和猴子SIP模型中乙醇饮用和应激/内分泌表型的改变是由大脑基因表达网络的适应性反应引起的，从而产生了一个新的适应设定值。该项目的目的是通过在Grant博士的BXD小鼠和恒河猴样本（项目1）中对CIE治疗的表达谱分析，与Williams博士的项目10的RNA-Seq数据共同分析结果，以及使用病毒载体基因传递测试候选基因，包括Gsk3P，来定义CIE和猴子SIP模型中适应变化的新基因网络。

DESCRIPTION (provided by applicant): An underlying premise of the INIA-Stress consortium is that progression to abusive ethanol consumption is, at least in part, accompanied and perhaps caused by alterations in an organism's response to stress, including the stress of excessive ethanol intake/withdrawal. We propose that changes in brain gene expression networks are an important part of allostatic mechanisms leading to progressive ethanol consumption and aberrant responses to stress. We have previously used genetic and genomic approaches across brain regions of BXD recombinant inbred panel to define robust gene networks regulated by acute ethanol and relate these to ethanol behaviors, particularly regarding responses to stress. We have also identified significant overlap in expression responses to acute ethanol in mice and altered gene expression patterns seen in a primate model of excessive ethanol intake (SIP) developed by Dr. Grant, the PI of the INIA-Stress consortium. Furthermore, very recent pilot array studies in BXD mice exposed to multiple cycles of the chronic intermittent ethanol vapor (CIE) model of excessive ethanol consumption have identified remarkable homology with results from acute ethanol exposure and our data from cynomolgus macaque. Those studies have generated gene networks that allow testing initial major "hub" genes for their possible role in modifying ethanol consumption and response to stress in the CIE model. For example, we recently identified Gsk3p as an important regulator of ethanol consumption and withdrawal-induced anxiety, using AAV viral vector gene delivery studies. Based on these findings, we propose the following Organizing Hypothesis: Altered ethanol drinking and stress/endocrine phenotypes in the mouse CIE and monkey SIP models result from (and cause) adaptive responses in brain gene expression networks, resulting in a new allostatic set point. The aims of this project will define new gene networks underlying allostatic changes in the CIE and monkey SIP models by expression profiling of CIE treatment across the BXD mouse panel and Rhesus Macaque samples of Dr. Grant (Project 1), co-analysis of results with RNA-Seq data of Dr. Williams' Project 10, and testing of candidates, including Gsk3P, using viral vector gene delivery.