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

大鼠动物模型

• 批准号: 9242267
• 负责人: RICHARD LOWELL BELL
• 金额: $ 37.05万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242267
• 关键词: Address; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Behavioral; Cause of Death; Centers for Disease Control and Prevention (U.S.); Companions; Complementary DNA; Development; Electrophysiology (science); Environment; Ethanol; FDA approved; Family; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Genetic screening method; Genomics; Goals; Heavy Drinking; Human; Immune; Immune Targeting; Individual; Inflammation; Infusion procedures; Interdisciplinary Study; Interleukin Receptor; Measures; Medial; Mediating; Molecular; Molecular Target; Mus; Neuroimmune; Neurosciences; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Prefrontal Cortex; Primates; Proteomics; Rattus; Recording of previous events; Research; Research Personnel; Resources; Running; Signal Transduction; Stress; Techniques; Testing; Toll-like receptors; Work; addiction; alcohol use disorder; disorder prevention; drinking behavior; drug testing; genetic manipulation; genetics of alcoholism; heuristics; innovation; phosphodiesterase IV; small hairpin RNA; small molecule; synergism

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.

根据疾病控制和预防中心(CDC)的数据，酒精使用障碍(AUD)继续 是美国第三大死因。美国儿童遗传学合作研究的多项研究 酒精中毒(COGA)和成瘾研究：基因和环境(SAGE)证实了作为一个个体 有家族病史的酗酒(FHP)是发展和发展的关键、可预测的决定因素 AUD的表达。选择性繁殖的偏爱酒精的P大鼠，以及程度较轻的高酒精- 饮酒使大鼠品系符合酒精中毒有效动物模型的标准，并表现出一定的遗传-- 在FHP个体中观察到与行为和生理相关的表型。这一核心是一项研究 酒精中毒综合神经科学倡议(INIA-神经免疫[INIA-N])联盟的资源。 这个研究资源的具体目标将测试(1)用靶向小分子治疗的效果 对P和HAD大鼠过量饮酒的影响，(2)shRNA和/或cDNA(TO)的输注 分别下调或上调靶基因表达水平)到扩展的 杏仁核(Ext-Amyg)和内侧前额叶皮质(MPFC)对P和HAD大鼠过量饮用乙醇的影响 和(3)与戴恩·梅菲尔德和其他U01密切合作，识别神经免疫信号，和/或他们的 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 以及正在进行的针对过度饮酒的基因组和蛋白质组研究。到目前为止观察到的一些目标 与INIA-N作为一个整体匹配，包括Toll样受体[Toll样受体]，白细胞介素受体[ILRs]， 磷酸二酯酶4[PDE4]和过氧化物酶体增殖物激活受体[PPAR]。这个核心将会工作 与U01组件和U24“电生理核心”密切合作，解决相关的研究问题 由各自的U01和/或管理核心提出。这是一个重要的核心，将提供重要的 AUD中神经免疫信号的验证和启发式信息，以及遗传上的 尤其是易感的受试者。此外，这个核心将评估梅菲尔德建议的化合物 INIA-N正在进行的工作中揭示了免疫靶标的LINCS分析和操纵者。这是一个高度的 一个创新的项目，使用最先进的技术选择性地改变“目标”基因的表达 在多代遗传选择(P，HAD1和HAD2)FHP大鼠的离散CNS亚区内。这 U24 CORE提供与INIA-N调查人员的协同，包括Blednov，Crabbe，Hitzemann， 基弗、拉塞克、梅森、梅菲尔德、莫里塞特、费弗鲍姆和罗伯托，以及INIA-Stress的贝克尔/洛佩兹。