We propose to use the power and ease of C. elegans genetics in a core capacity to extend existing substance abuse research in new directions. We will use this genetically-tractable organism to pursue novel areas of study related to funded projects and to answer other questions not easily addressed in a mammalian system that are posed by ourselves and the large group of drug abuse researchers at this and neighboring institutions. The end goal of this core-provided research will be to better understand mechanisms of action of drugs of abuse, including identification and elaboration of genes and pathways that are important in drug effects, and to provide a biological system where alterations in nervous system function can be genetically controlled with ease to aid in drug development and drug selection. This core will allow investigators who would not otherwise make use of C. elegans in their own laboratories the opportunity to collaborate with scholars who have extensive experience with this organism and together pursue these novel lines of research investigation. There are three main areas of focus proposed by this C. elegans genetics core. 1) To use C. elegans genetics, pharmacology and a battery of phenotypic assays to understand the effects of alterations in specific genes, specific biological pathways or to better understand the effect of a drug with unclear mechanisms of action. This approach will link the action of drugs with well characterized biological pathways and neurotransmitter systems that can be dissected further using C. elegans genetics. 2) To use C. elegans to carry out reverse and forward genetic screens for genes that are important in mediating phenotypic effects of interest, such as drug-induced phenotypes, or phenotypes produced through alteration of a biological system related to substance abuse. This approach has the potential to identify genes not previously known to be involved with specific drug effects. 3) To use C. elegans to develop living bioassays to take advantage of whole organism drug effects and integration of to vivo biological systems. This approach will allow for refinement of drug development strategies using a whole animal system. These approaches will bring the innovation associated with this powerful genetic system to substance abuse research and generate significant novel findings that will allow researchers to better understand the genetic underpinnings of the mechanisms of action of drugs of abuse.
C. elegans is a powerful genetic model system with a relatively simple nervous system that shares many conserved components with the human brain. Genetic approaches utilizing mutants and transgene techniques will be used to identify genes and biological processes that are important for the action of drugs of abuse and to allow for the development of drugs used to treat substance abuse.
|Donvito, Giulia; Nass, Sara R; Wilkerson, Jenny L et al. (2018) The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain. Neuropsychopharmacology 43:52-79|
|Wolstenholme, Jennifer T; Bowers, M Scott; Pais, Alexander B et al. (2018) Dietary Omega-3 Fatty Acids Differentially Impact Acute Ethanol-Responsive Behaviors and Ethanol Consumption in DBA/2J Versus C57BL/6J Mice. Alcohol Clin Exp Res :|
|Hermes, Douglas J; Xu, Changqing; Poklis, Justin L et al. (2018) Neuroprotective effects of fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat model of neuroAIDS. Neuropharmacology 141:55-65|
|Mischel, Ryan A; Dewey, William L; Akbarali, Hamid I (2018) Tolerance to Morphine-Induced Inhibition of TTX-R Sodium Channels in Dorsal Root Ganglia Neurons Is Modulated by Gut-Derived Mediators. iScience 2:193-209|
|Shin, Myungsun; Snyder, Helena W; Donvito, Giulia et al. (2018) Liposomal Delivery of Diacylglycerol Lipase-Beta Inhibitors to Macrophages Dramatically Enhances Selectivity and Efficacy in Vivo. Mol Pharm 15:721-728|
|Gonek, Maciej; McLane, Virginia D; Stevens, David L et al. (2018) CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward. Brain Behav Immun 69:124-138|
|Curry, Zachary A; Wilkerson, Jenny L; Bagdas, Deniz et al. (2018) Monoacylglycerol Lipase Inhibitors Reverse Paclitaxel-Induced Nociceptive Behavior and Proinflammatory Markers in a Mouse Model of Chemotherapy-Induced Neuropathy. J Pharmacol Exp Ther 366:169-183|
|Cooper, Ziva D; Poklis, Justin L; Liu, Fei (2018) Methodology for controlled administration of smoked synthetic cannabinoids JWH-018 and JWH-073. Neuropharmacology 134:92-100|
|Xu, Xiaoyang; Zhang, Aolin; Halquist, Matthew S et al. (2017) Simvastatin promotes NPC1-mediated free cholesterol efflux from lysosomes through CYP7A1/LXR? signalling pathway in oxLDL-loaded macrophages. J Cell Mol Med 21:364-374|
|Ahmad, Ashfaq; Daneva, Zdravka; Li, Guangbi et al. (2017) Stimulation of diuresis and natriuresis by renomedullary infusion of a dual inhibitor of fatty acid amide hydrolase and monoacylglycerol lipase. Am J Physiol Renal Physiol 313:F1068-F1076|
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