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Browsing by Author "McClintick, Jeanette N."
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Item The Access Technology Program of the Indiana Clinical Translational Sciences Institute (CTSI): A model to facilitate access to cutting-edge technologies across a state(Cambridge, 2021) Orschell, Christie M.; Skaar, Todd C.; DeFord, Melanie E.; Ybe, Joel; Driscol, Julie; Drury, Christine; Reeves, Lilith; Willis, Monte S.; Reiter, Jill L.; York, Jenna; Orr, Rob; McClintick, Jeanette N.; Sors, Thomas G.; Hunt, Joe; Cornetta, Kenneth; Shekhar, Anantha; Medicine, School of MedicineIntroduction: Access to cutting-edge technologies is essential for investigators to advance translational research. The Indiana Clinical and Translational Sciences Institute (CTSI) spans three major and preeminent universities, four large academic campuses across the state of Indiana, and is mandate to provide best practices to a whole state. Methods: To address the need to facilitate the availability of innovative technologies to its investigators, the Indiana CTSI implemented the Access Technology Program (ATP). The activities of the ATP, or any program of the Indiana CTSI, are challenged to connect technologies and investigators on the multiple Indiana CTSI campuses by the geographical distances between campuses (1–4 hr driving time). Results: Herein, we describe the initiatives developed by the ATP to increase the availability of state-of-the-art technologies to its investigators on all Indiana CTSI campuses, and the methods developed by the ATP to bridge the distance between campuses, technologies, and investigators for the advancement of clinical translational research. Conclusions: The methods and practices described in this publication may inform other approaches to enhance translational research, dissemination, and usage of innovative technologies by translational investigators, especially when distance or multi-campus cultural differences are factors to efficient application.Item Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review(Wiley, 2018-12) Edenberg, Howard J.; McClintick, Jeanette N.; Biochemistry and Molecular Biology, School of MedicineAlcohol use disorders (AUD) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic contribution to risk is substantial, most individual variations make only very small contributions. By far the strongest contributors are functional variations in two genes involved in alcohol (ethanol) metabolism. A functional variant in alcohol dehydrogenase 1B (ADH1B) is protective in people of European and Asian descent, and a different functional variant in the same gene is protective in those of African descent. A strongly protective variant in aldehyde dehydrogenase 2 (ALDH2) is essentially only found in Asians. This highlights the need to study a wide range of populations. The likely mechanism of protection against heavy drinking and AUD in both cases is alteration in the rate of metabolism of ethanol that at least transiently elevates acetaldehyde. Other ADH and ALDH variants, including functional variations in ADH1C, have also been implicated in affecting drinking behavior and risk for alcoholism. The pattern of linkage disequilibrium in the ADH region, and the differences among populations, complicate analyses, particularly of regulatory variants. This critical review focuses upon the ADH and ALDH genes as they affect AUDs.Item Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats(BMC, 2010-02-03) Liang, Tiebing; Kimpel, Mark W.; McClintick, Jeanette N.; Skillman, Ashley R.; McCall, Kevin; Edenberg, Howard J.; Carr, Lucinda G.; Medicine, School of MedicineSelectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats differ greatly in alcohol preference, in part due to a highly significant quantitative trait locus (QTL) on chromosome 4. Alcohol consumption scores of reciprocal chromosome 4 congenic strains NP.P and P.NP correlated with the introgressed interval. The goal of this study was to identify candidate genes that may influence alcohol consumption by comparing gene expression in five brain regions of alcohol-naïve inbred alcohol-preferring and P.NP congenic rats: amygdala, nucleus accumbens, hippocampus, caudate putamen, and frontal cortex. Results Within the QTL region, 104 cis-regulated probe sets were differentially expressed in more than one region, and an additional 53 were differentially expressed in a single region. Fewer trans-regulated probe sets were detected, and most differed in only one region. Analysis of the average expression values across the 5 brain regions yielded 141 differentially expressed cis-regulated probe sets and 206 trans-regulated probe sets. Comparing the present results from inbred alcohol-preferring vs. congenic P.NP rats to earlier results from the reciprocal congenic NP.P vs. inbred alcohol-nonpreferring rats demonstrated that 74 cis-regulated probe sets were differentially expressed in the same direction and with a consistent magnitude of difference in at least one brain region. Conclusions Cis-regulated candidate genes for alcohol consumption that lie within the chromosome 4 QTL were identified and confirmed by consistent results in two independent experiments with reciprocal congenic rats. These genes are strong candidates for affecting alcohol preference in the inbred alcohol-preferring and inbred alcohol-nonpreferring rats.Item Changes in Gene Expression within the Extended Amygdala following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats(Elsevier, 2014-02) McBride, William J.; Kimpel, Mark W.; McClintick, Jeanette N.; Ding, Zheng-Ming; Edenberg, Howard J.; Liang, Tiebing; Rodd, Zachary A.; Bell, Richard L.; Department of Psychiatry, IU School of MedicineThe objective of this study was to determine changes in gene expression within the extended amygdala following binge-like alcohol drinking by male adolescent alcohol-preferring (P) rats. Starting at 28 days of age, P rats were given concurrent access to 15 and 30 % ethanol for 3 one-h sessions/day for 5 consecutive days/week for 3 weeks. Rats were killed by decapitation 3 h after the first ethanol access session on the 15th day of drinking. RNA was prepared from micropunch samples of the nucleus accumbens shell (Acb-sh) and central nucleus of the amygdala (CeA). Ethanol intakes were 2.5 – 3.0 g/kg/session. There were 154 and 182 unique named genes that significantly differed (FDR = 0.2) between the water and ethanol group in the Acb-sh and CeA, respectively. Gene Ontology (GO) analyses indicated that adolescent binge drinking produced changes in biological processes involved with cell proliferation and regulation of cellular structure in the Acb-sh, and in neuron projection and positive regulation of cellular organization in the CeA. Ingenuity Pathway Analysis indicated that, in the Acb-sh, there were several major intracellular signaling pathways (e.g., cAMP-mediated and protein kinase A signaling pathways) altered by adolescent drinking, with 3-fold more genes up-regulated than down-regulated in the alcohol group. The cAMP-mediated signaling system was also up-regulated in the CeA of the alcohol group. Weighted gene co-expression network analysis indicated significant G-protein coupled receptor signaling and transmembrane receptor protein kinase signaling categories in the Acb-sh and CeA, respectively. Overall, the results of this study indicated that binge-like alcohol drinking by adolescent P rats is differentially altering the expression of genes in the Acb-sh and CeA, some of which are involved in intracellular signaling pathways and may produce changes in neuronal function.Item Differential gene expression in the nucleus accumbens with ethanol self-administration in inbred alcohol-preferring rats(Elsevier, 2008-06) Rodd, Zachary A.; Kimpel, Mark W.; Edenberg, Howard J.; Bell, Richard L.; Strother, Wendy N.; McClintick, Jeanette N.; Carr, Lucinda G.; Liang, Tiebing; McBride, William J.; Department of Psychiatry, IU School of MedicineThe current study examined the effects of operant ethanol (EtOH) self-administration on gene expression in the nucleus accumbens (ACB) and amygdala (AMYG) of inbred alcohol-preferring (iP) rats. Rats self-trained on a standard two-lever operant paradigm to administer either water-water, EtOH (15% v/v)-water, or saccharin (SAC; 0.0125% g/v)-water. Animals were killed 24 hr after the last operant session, and the ACB and AMYG dissected; RNA was extracted and purified for microarray analysis. For the ACB, there were 513 significant differences at the p < 0.01 level in named genes: 55 between SAC and water; 215 between EtOH and water, and 243 between EtOH and SAC. In the case of the AMYG (p < 0.01), there were 48 between SAC and water, 23 between EtOH and water, and 63 between EtOH and SAC group. Gene Ontology (GO) analysis indicated that differences in the ACB between the EtOH and SAC groups could be grouped into 15 significant (p < 0.05) categories, which included major categories such as synaptic transmission, cell and ion homeostasis, and neurogenesis, whereas differences between the EtOH and water groups had only 4 categories, which also included homeostasis and synaptic transmission. Several genes were in common between the EtOH and both the SAC and water groups in the synaptic transmission (e.g., Cav2, Nrxn, Gabrb2, Gad1, Homer1) and homeostasis (S100b, Prkca, Ftl1) categories. Overall, the results suggest that changes in gene expression in the ACB of iP rats are associated with the reinforcing effects of EtOH.Item Differential miRNA Expression in Cells and Matrix Vesicles in Vascular Smooth Muscle Cells from Rats with Kidney Disease(PLOS, 2015-06-26) Chaturvedi, Praneet; Chen, Neal X.; O’Neill, Kalisha; McClintick, Jeanette N.; Moe, Sharon M.; Janga, Sarath Chandra; Department of BioHealth Informatics, School of Informatics and ComputingVascular calcification is a complex process and has been associated with aging, diabetes, chronic kidney disease (CKD). Although there have been several studies that examine the role of miRNAs (miRs) in bone osteogenesis, little is known about the role of miRs in vascular calcification and their role in the pathogenesis of vascular abnormalities. Matrix vesicles (MV) are known to play in important role in initiating vascular smooth muscle cell (VSMC) calcification. In the present study, we performed miRNA microarray analysis to identify the dysregulated miRs between MV and VSMC derived from CKD rats to understand the role of post-transcriptional regulatory networks governed by these miRNAs in vascular calcification and to uncover the differential miRNA content of MV. The percentage of miRNA to total RNA was increased in MV compared to VSMC. Comparison of expression profiles of miRNA by microarray demonstrated 33 miRs to be differentially expressed with the majority (~ 57%) of them down-regulated. Target genes controlled by differentially expressed miRNAs were identified utilizing two different complementary computational approaches Miranda and Targetscan to understand the functions and pathways that may be affected due to the production of MV from calcifying VSMC thereby contributing to the regulation of genes by miRs. We found several processes including vascular smooth muscle contraction, response to hypoxia and regulation of muscle cell differentiation to be enriched. Signaling pathways identified included MAP-kinase and wnt signaling that have previously been shown to be important in vascular calcification. In conclusion, our results demonstrate that miRs are concentrated in MV from calcifying VSMC, and that important functions and pathways are affected by the miRs dysregulation between calcifying VSMC and the MV they produce. This suggests that miRs may play a very important regulatory role in vascular calcification in CKD by controlling an extensive network of post-transcriptional targets.Item Effects of chronic intermittent ethanol exposure and withdrawal on neuroblastoma cell transcriptome(Elsevier, 2020-06) McClintick, Jeanette N.; Thapa, Kriti; Liu, Yunlong; Xuei, Xiaoling; Edenberg, Howard J.; Biochemistry and Molecular Biology, School of MedicineCycles of heavy drinking and abstinence can lead to ethanol abuse disorder. We studied the effects of chronic intermittent ethanol exposure (CIE) over three weeks on neuroblastoma cells, using an ethanol concentration frequently attained in binge drinking (40 mM, 184 mg/dl). There were many changes in gene expression but most were small. CIE affected pathways instrumental in the development or plasticity of neurons, including axonal guidance, reelin signaling and synaptogenesis. Genes involved in dopamine and serotonin signaling were also affected. Changes in transporters and receptors could dampen both NMDA and norepinephrine transmissions. Decreased expression of the GABA transporter SLC6A11 could increase GABA transmission and has been associated with a switch from sweet drinking to ethanol consumption in rats. Ethanol increased stress responses such as unfolded protein response. TGF-β and NFκB signaling were increased. Most of the genes involved in cholesterol biosynthesis were decreased in expression. Withdrawal for 24 h after CIE caused most of the CIE-induced expression changes to move back toward unexposed levels.Item Effects of filtering by Present call on analysis of microarray experiments(BioMed Central, 2006-01-31) McClintick, Jeanette N.; Edenberg, Howard J.; Biochemistry and Molecular Biology, School of MedicineBackground Affymetrix GeneChips® are widely used for expression profiling of tens of thousands of genes. The large number of comparisons can lead to false positives. Various methods have been used to reduce false positives, but they have rarely been compared or quantitatively evaluated. Here we describe and evaluate a simple method that uses the detection (Present/Absent) call generated by the Affymetrix microarray suite version 5 software (MAS5) to remove data that is not reliably detected before further analysis, and compare this with filtering by expression level. We explore the effects of various thresholds for removing data in experiments of different size (from 3 to 10 arrays per treatment), as well as their relative power to detect significant differences in expression. Results Our approach sets a threshold for the fraction of arrays called Present in at least one treatment group. This method removes a large percentage of probe sets called Absent before carrying out the comparisons, while retaining most of the probe sets called Present. It preferentially retains the more significant probe sets (p ≤ 0.001) and those probe sets that are turned on or off, and improves the false discovery rate. Permutations to estimate false positives indicate that probe sets removed by the filter contribute a disproportionate number of false positives. Filtering by fraction Present is effective when applied to data generated either by the MAS5 algorithm or by other probe-level algorithms, for example RMA (robust multichip average). Experiment size greatly affects the ability to reproducibly detect significant differences, and also impacts the effect of filtering; smaller experiments (3–5 samples per treatment group) benefit from more restrictive filtering (≥50% Present). Conclusion Use of a threshold fraction of Present detection calls (derived by MAS5) provided a simple method that effectively eliminated from analysis probe sets that are unlikely to be reliable while preserving the most significant probe sets and those turned on or off; it thereby increased the ratio of true positives to false positives.Item Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes(Karger Publishers, 2016-10) Anand, Amit; McClintick, Jeanette N.; Murrell, Jill; Karne, Harish; Nurnberger, John I.; Edenberg, Howard J.; Psychiatry, School of MedicineBackground This study investigated the effect of lithium monotherapy on peripheral lymphocyte gene expression in bipolar disorder (BD). Method Twenty-two medication-free bipolar subjects (11 hypomanic, 11 depressed) were started on lithium monotherapy. Closely matched healthy subjects (n = 15) were included as controls but did not receive treatment. Blood RNA samples were collected at baseline and after 2 and 8 weeks of treatment. RNA expression was measured using the Affymetrix GeneChip® Human Gene 1.0 ST Array followed by Ingenuity pathways analysis. The results for the contrast of weeks 2 and 8 were not significantly different and were combined. Results In BD subjects, 56 genes showed significant (false discovery rate <0.1) expression changes from baseline; the effect sizes and directions for all of these were similar at weeks 2 and 8. Among these were immune-related genes (IL5RA, MOK, IFI6, and RFX2), purinergic receptors (P2RY14, P2RY2, and ADORA3) and signal transduction-related genes (CAMK1 and PIK3R6). Pathway and upstream regulator analysis also revealed that lithium altered several immune- and signal transduction-related functions. Differentially expressed genes did not correlate with week 8 clinical response, but other genes involved in protein synthesis and degradation did. Conclusion Peripheral gene expression may serve as a biomarker of lithium effect.Item THE EIF2 KINASE PERK AND THE INTEGRATED STRESS RESPONSE FACILITATE ACTIVATION OF ATF6 DURING ENDOPLASMIC RETICULUM STRESS(Office of the Vice Chancellor for Research, 2012-04-13) Teske, Brian F.; Wek, Ronald C.; Wek, Sheree A.; Bunpo, Piyawan; Cundiff, Judy K.; McClintick, Jeanette N.; Anthony, Tracy G.; Wek, Ronald C.Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves changes in gene expression aimed at expanding the ER protein processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. Mutations of these ER stress sensors have been linked to diabetes, cancer and neurodegenerative diseases. Consequently, understanding the regulation of these three pathways has substantial therapeutic potential for development of biomarkers and pharmaceuticals for management of these conditions. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins. PERK phosphorylation of eIF2 (eIF2~P) also induces preferential translation of ATF4, a transcription activator of the UPR. In this study we show that the PERK/eIF2~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse biological defects associated with loss of PERK.
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