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.
The Rat Animal Models & Drug and Gene Testing Core Research Resource for INIA-N provides synergy with INIA-N?s multidisciplinary research components. It will do this by testing the effects of pharmacological and genetic manipulations of immune and inflammation targets identified by INIA-N on excessive alcohol drinking by subjects (P and HAD rats) genetically predisposed for excessive alcohol intake with the long-term goal of repurposing FDA-approved medications to treat alcoholism.
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