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

描述（由申请人提供）：INIA-应激联合体的一个基本前提是，滥用乙醇的进展至少部分地伴随着生物体对应激反应的改变，可能是由生物体对应激反应的改变引起的，包括过量乙醇摄入/戒断的应激。我们认为，大脑基因表达网络的变化是导致渐进性乙醇消耗和对压力的异常反应的变稳态机制的重要组成部分。我们之前已经使用遗传和基因组方法在BXD重组近交系面板的大脑区域中定义了由急性乙醇调节的强大基因网络，并将这些与乙醇行为相关，特别是关于对压力的反应。我们还确定了小鼠对急性乙醇的表达反应的显著重叠，以及由INIA-Stress财团的PI Grant博士开发的过量乙醇摄入（SIP）灵长类动物模型中观察到的基因表达模式改变。此外，最近在暴露于多个周期的慢性间歇性乙醇蒸汽（CIE）模型的过量乙醇消耗的BXD小鼠中进行的试验性阵列研究已经确定了与急性乙醇暴露的结果和食蟹猴数据的显著同源性。这些研究已经产生了基因网络，允许测试初始主要“枢纽”基因在CIE模型中改变乙醇消耗和应激反应的可能作用。例如，我们最近使用AAV病毒载体基因递送研究确定Gsk 3 p是乙醇消耗和戒断诱导的焦虑的重要调节剂。基于这些研究结果，我们提出了以下组织假说：改变乙醇饮用和压力/内分泌表型在小鼠CIE和猴子SIP模型的结果（和原因）在大脑基因表达网络的适应性反应，导致一个新的非稳态设定点。本项目的目的是通过对Grant博士（项目1）的BXD小鼠样本组和恒河猴样本进行CIE治疗的表达谱分析，对结果与威廉姆斯博士项目10的RNA-Seq数据进行共分析，并使用病毒载体基因递送测试候选物（包括Gsk 3 P），从而定义CIE和猴SIP模型中变稳态变化的新基因网络。

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.