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The three stages of addiction seen as a hypothetical progression through drug-induced changes in gene expression.

from Kalivas and Volkow, 2005. “Binge” Drinking (DID). “Dependence” (WID). INIA Animal Models. “Genetic Predisposition” Selected lines, Inbred strains, Genetically modified mice.

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The three stages of addiction seen as a hypothetical progression through drug-induced changes in gene expression.

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  1. from Kalivas and Volkow, 2005 “Binge” Drinking (DID) “Dependence” (WID) INIA Animal Models “Genetic Predisposition” Selected lines, Inbred strains, Genetically modified mice The three stages of addiction seen as a hypothetical progression through drug-induced changes in gene expression.

  2. Integration of INIA gene expression datasets: Focus on Excessive Alcohol Consumption 1. CORE ANALYSES 2. MAIN RESULTS 3. FILTERS 4. INFORMATICSGOAL: “Genetics” Domain (ethanol-naïve) Identify genes shown to be “functional” in neuroscience (addiction research), but new to alcohol research Rats iP/iNP Brain Regions (ethanol-naïve) 1. Literature Search 2. Cell Type – and Tissue – Specific Databases: ABA, MNED 3. Over- representation of Functional Groups and Chromosomal Locations, Alcohol QTLs 4. Etc… Mouse Meta- Analysis: Selected Lines and Inbred Strains Whole Brain Mouse BXD RI Correlations with Pref. drinking Whole Brain Genes influenced by Genetics (ethanol-naive) Indiana Group Mulligan et al., 2006 Saba et al., 2006 WebQTL (2 datasets: UCHSC and INIA East) Mouse Congenic Ch9 Whole Brain (ethanol-naïve) “Binge” Domain Genes influenced by ethanol Binge Drinking 1 Mouse B6 DID 1 day Brain Regions Mouse FVB/B6 F1 DID 4 days Whole Brain 2 4 Mulligan et al., 2006 Top Candidate Gene Cards Rats iP Brain Regions alcohol operant Genes associated with Dependence on ethanol 3 Ponomarev et al. In progress Bergeson et al. Data collected Gene 1 Gene 2 Indiana Group “Dependence” Domain Human Alcoholics Frontal Cortex Gene 3 Gene 4 Mouse D2 WID i.g. Brain Regions Mouse B6 WID standard Whole Brain Mouse HAP/LAP WID standard Whole Brain Liu et al., 2005 etc… Other Filters Hoffman et al. Planned Bergeson et al. Planned Rhodes et al. In progress Indiana Group: Edenberg et al., 2005 Rodd et al., 2006 Kimpel et al., 2007

  3. INIA Genetic Targets for Excessive Alcohol Consumption Homer2: Homer homolog 2 (Drosophila) is a member of the homer family of dendritic proteins. Modulates glutamate signaling in the postsynaptic density. Regulates synaptic plasticity. Scn4b: Sodium channel, type IV, beta is an auxiliary subunit that alters the channel kinetics of voltage-gated alpha subunit. Gnb1: Guanine nucleotide binding protein, beta polypeptide 1 encodes a beta subunit, an important regulator of alpha subunit in the heterotrimeric G-proteins. Hyou1: Hypoxia up-regulated 1 belongs to the heat shock protein 70 family. It is thought to play an important role in protein folding and secretion in the ER. Paqr7, Paqr9: Progestin and adipoQ receptor family member VII and IX encode functional receptors with a broad range of apparent ligand specificities. They may mediate nongenomic actions of steroids and hormone-like activities of the globular protein adipoQ, respectively. B2m: Beta-2 microglobulin is a low molecular weight protein that is present on the surface of nearly all nucleated cells. Its concentration in biological fluids is related to the rate of cell membrane renovation, and high levels reflect an increased cellular turnover. High B2m concentrations in CSF have been described in different inflammatory or neoplastic CNS disorders. Il1rn: Interleukin 1 receptor antagonist is a member of the interleukin 1 cytokine family. It inhibits the activities of interleukin 1 and modulates Il1 - related immune and inflammatory responses. Ctss, Ctsf: Cathepsins S and F are cysteine proteinases that represent a major component of the lysosomal proteolytic system.

  4. Filters Core Analyses INIA Genetic Targets for Excessive Alcohol Consumption Values are p-values based on either meta-analyses for Cores or t-tests for Filters. * Shown is a t-test p-value from Bergeson et al., (not published), because this is the only “Binge” data set available so far. ns = not significant; np = not present on array; fo = filtered out (did not pass filters) Red = either higher expression values in alcohol preferring subjects or/and up-regulation after alcohol and Green = either higher expression values in alcohol non-preferring subjects or/and down-regulation after alcohol.

  5. INIA Potential Future Targets for High Alcohol Consumption Kcnip3: Kv channel interacting protein 3, calsenilin is involved in regulation of a) neuronal excitability, b) prodynorphin transcription, c) presenilin-dependent gamma-cleavage, d) long-term potentiation in the dentate gyrus. Ngef: Neuronal guanine nucleotide exchange factor, ephexin is involved in regulation of actin cytoskeleton through acting on Rho-GTPase. Expressed in a cell type – specific manner. Park7: Parkinson disease (autosomal recessive, early onset) 7, DJ-1 is associated with various cellular processes, including response to oxidative stress, cellular transformation and RNA binding. Loss of functional protein was shown to cause autosomal recessive Parkinson's disease. Trak1: Trafficking protein, kinesin binding 1 interacts with and regulates trafficking of GABAA receptors. Clu: Clusterin, apolipoprotein J is a ubiquitous multifunctional glycoprotein capable of interacting with a broad spectrum of molecules. It is implicated in various physiological processes including cell proliferation, differentiation, tissue regeneration, and aging. Kcnq2: Potassium voltage-gated channel, subfamily Q, member 2 is associated with a related protein (Kcnq3) to form the M channel which is a slowly activating and deactivating potassium channel that is inhibited by M1 muscarinic acetylcholine receptors and plays a critical role in regulation of neuronal excitability. Kcnk1: Potassium channel, subfamily K, member 1, TWIK-1 encodes a member of the superfamily of potassium channel proteins containing two pore-forming P domains. It mediates the inhibition of the excitability of some cortical neurons by 5-HT.

  6. Filters Core Analyses INIA Potential Future Targets for High Alcohol Consumption Values are p-values based on either meta-analyses for Cores or t-tests for Filters. * Shown is a t-test p-value from Bergeson et al., (not published), because this is the only “Binge” data set available so far. ns = not significant; np = not present on array; fo = filtered out (did not pass filters) Red = either higher expression values in alcohol preferring subjects or/and up-regulation after alcohol and Green = either higher expression values in alcohol non-preferring subjects or/and down-regulation after alcohol.

  7. A more extensive INIA gene list (n=53) Indiana Colorado Homer2 Rab14 C1qb Texas Scn1b/2b/4b Ptgs1 Gnb1/b3 Psmb7 1110032A03Rik C1qb Sfpq Id3 Fabp3 Homer2 Ctss, Ctsf Gnb1 Park7 Nudc Scn4b Kcnip3 Egr4 Dhrs3 Ube2j2 Ppm1b Fbxo2 Gnb1 Ngef Prkce Gnb1/Gnl1 Scn4b Hyou1 Park7 Rab15 Git2 Rdh11 Pik3ca Paqr7, Paqr9 Trak1 Cep63 Nr4a1 Ptpn11 P2rx4 B2m Gria1 Clu C1qc Nrgn Mc4r Il1rn Kcnq2 Ncdn Thra D930028F11Rik Atp2b3 Kcnk1 Stx5a

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