Rat Animal Models & Drug and Gene Testing Core (RAM-DGTC)

根据疾病控制和预防中心（CDC），酒精使用障碍（AUD）继续 是美国第三大死亡原因。 酒精中毒（COGA）和成瘾研究：基因和环境（SAGE）证实，作为一个个体， 具有酒精中毒家族史阳性（FHP）是发展的关键，可预测的决定因素， AUD的表达。选择性繁殖的嗜酒精P大鼠和在较小程度上，高酒精- 饮用HAD大鼠系满足为有效的酒精中毒动物模型提出的标准并显示出某些遗传， 在FHP个体中观察到的行为和生理相关表型。此核心是一项研究 酒精中毒综合神经科学倡议（INIA-Neuroimmune [INIA-N]）联盟。 本研究资源的具体目标将测试（1）目标小分子治疗的效果 P和HAD大鼠过量饮用乙醇（EtOH），（2）输注shRNA和/或cDNA（以 分别下调或上调靶基因表达水平）进入延伸的细胞的亚区。 杏仁核（Ext-Amyg）和内侧前额叶皮层（mPFC）对P和HAD大鼠过量乙醇饮酒的影响， 和（3）与Dayne Mayfield和其他U 01密切合作，识别神经免疫信号传导，和/或它们的神经免疫信号传导。 途径，与发生AUD的遗传易感性相关的靶点。为此，我们将使用以前的 以及正在进行的过量饮酒的基因组和蛋白质组学研究。迄今观察到的一些目标 与INIA-N的那些作为一个整体匹配，包括Toll样受体[TLR]，白细胞介素受体[ILR]， 磷酸二酯酶4 [PDE 4]和过氧化物酶体增殖物激活受体[PPAR]。这个核心会起作用 与U 01组件和U24“电生理学核心”密切合作，以解决相关的研究问题 由各自的U 01和/或行政核心提出。这是一个重要的核心，将提供重要的 验证和启发性信息的神经免疫信号在AUD的一般，以及在遗传 尤其是易受感染的人此外，该核心将评估梅菲尔德提出的化合物， INIA-N正在进行的工作中揭示了LINCS分析和免疫靶点操纵器。这是一个高度 创新项目，使用最先进的技术来选择性地改变“目标”基因的表达 在多代遗传选择的（P，HAD 1和HAD 2）FHP大鼠的离散CNS亚区中。这 U24核心提供了与一些INIA-N研究人员的协同作用，包括Blednov，Crabbe，Hitzemann， Kieffer、Lasek、Mason、Mayfield、Morrisett、Pfefferbaum和Roberto，以及INIA-Stress的Becker/洛佩斯。

According to the Centers for Disease Control and Prevention (CDC), alcohol use disorder (AUD) continues to be the third leading cause of death in the U.S. Multiple studies from the Collaborative Studies on Genetics of Alcoholism (COGA) and Study of Addiction: Genes and Environment (SAGE) confirm that being an individual with a family history positive (FHP) for alcoholism is a key, predictable determinant for the development and expression of AUD. The selectively bred alcohol-preferring P rat and, to a lesser extent, the high-alcohol- drinking HAD rat lines meet criteria put forth for a valid animal model of alcoholism and display certain genetic-, behavioral-, and physiological-related phenotypes observed in FHP individuals. This core is a Research Resource for the Integrative Neuroscience Initiative on Alcoholism (INIA-Neuroimmune [INIA-N]) consortium. The Specific Aims of this Research Resource will test the effects of (1) treatment with target small molecules on excessive ethanol (EtOH) drinking by P and HAD rats, (2) infusions of shRNA and/or cDNA (to downregulate or upregulate, respectively, target gene expression levels) into subregions of the extended amygdala (Ext-Amyg) and medial prefrontal cortex (mPFC) on excessive EtOH drinking by P and HAD rats, and (3) work closely with Dayne Mayfield’s, and others U01s, in identifying neuroimmune signaling, and/or their pathway, targets associated with a genetic predisposition to develop AUD. For this, we will use our previous and ongoing genomic and proteomic work for excessive alcohol drinking. Some of the targets observed so far match those of INIA-N as a whole including toll-like receptors [TLRs], interleukin receptors [ILRs], phosphodiesterase 4 [PDE4], and peroxisome proliferator-activated receptor [PPAR]. This core will work closely with U01 components and the U24 “Electrophysiology Core” to address pertinent research questions raised by respective U01s and/or the Administrative Core. This is a significant core that will provide important verification and heuristic information on neuroimmune signaling in AUD in general, as well as in genetically predisposed subjects in particular. Moreover, this Core will evaluate compounds suggested by Mayfield’s LINCS analysis and manipulators of immune targets revealed in ongoing work of INIA-N. This is a highly innovative project that uses state-of-the-art techniques to selectively alter the expression of “target” genes within discrete CNS subregions in multigenerational, genetically selected (P, HAD1 and HAD2) FHP rats. This U24 core provides synergy with a number of INIA-N investigators, including Blednov, Crabbe, Hitzemann, Kieffer, Lasek, Mason, Mayfield, Morrisett, Pfefferbaum, and Roberto, as well as Becker/Lopez of INIA-Stress.