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14 results on '"Reinhart, Veronica"'

3. A systematic survey of human tissue-specific gene expression and splicing reveals new opportunities for therapeutic target identification and evaluation

Author

Yang, Robert Y., Quan, Jie, Sodaei, Reza, Aguet, Francois, Segrè, Ayellet V., Allen, John A., Lanz, Thomas A., Reinhart, Veronica, Crawford, Matthew, Hasson, Samuel, Ardlie, Kristin G., Guigó, Roderic, and Xi, Hualin S.

Subjects
0303 health sciences, Alternative splicing, Tissue-Specific Gene Expression, RNA-Seq, Genome-wide association study, Computational biology, Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, RNA splicing, Identification (biology), 030217 neurology & neurosurgery, 030304 developmental biology, G protein-coupled receptor
Abstract

Differences in the expression of genes and their splice isoforms across human tissues are fundamental factors to consider for therapeutic target evaluation. To this end, we conducted a transcriptome-wide survey of tissue-specific gene expression and splicing events in the unprecedented collection of 8527 high-quality RNA-seq samples from the GTEx project, covering 36 human peripheral tissues and 13 brain subregions. We derived a weighted tissue-specificity scoring scheme accounting for the similarity of related tissues and inherent variability across individual samples. We showed that ~50.6% of all annotated human genes show tissue-specific expression, including many low abundance transcripts vastly underestimated by previous array-based expression atlases. As utilities for drug discovery, we demonstrated that tissue-specificity is a highly desirable attribute of validated drug targets and tissue-specificity can be used to prioritize disease-associated genes from genome-wide association studies (GWAS). Using brain striatum-specific gene expression as an example, we provided a template to leverage tissue-specific gene expression to identify novel therapeutic targets. Mining of tissue-specific splicing further reveals new opportunities for tissue-specific targeting. Thus, the high quality transcriptome atlas provided by the GTEx is an invaluable resource for drug discovery and systematic analysis anchored on the human tissue specific gene expression provides a promising avenue to identify novel therapeutic target hypotheses.

Published
2018

4. Design and optimization of selective azaindole amide M1 positive allosteric modulators

Author

Davoren, Jennifer E., O’Neil, Steven V., Anderson, Dennis P., Brodney, Michael A., Chenard, Lois, Dlugolenski, Keith, Edgerton, Jeremy R., Green, Michael, Garnsey, Michelle, Grimwood, Sarah, Harris, Anthony R., Kauffman, Gregory W., LaChapelle, Erik, Lazzaro, John T., Lee, Che-Wah, Lotarski, Susan M., Nason, Deane M., Obach, R. Scott, Reinhart, Veronica, Salomon-Ferrer, Romelia, Steyn, Stefanus J., Webb, Damien, Yan, Jiangli, and Zhang, Lei

Published
2016
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6. Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects

Author

Davoren, Jennifer E., primary, Lee, Che-Wah, additional, Garnsey, Michelle, additional, Brodney, Michael A., additional, Cordes, Jason, additional, Dlugolenski, Keith, additional, Edgerton, Jeremy R., additional, Harris, Anthony R., additional, Helal, Christopher J., additional, Jenkinson, Stephen, additional, Kauffman, Gregory W., additional, Kenakin, Terrence P., additional, Lazzaro, John T., additional, Lotarski, Susan M., additional, Mao, Yuxia, additional, Nason, Deane M., additional, Northcott, Carrie, additional, Nottebaum, Lisa, additional, O’Neil, Steven V., additional, Pettersen, Betty, additional, Popiolek, Michael, additional, Reinhart, Veronica, additional, Salomon-Ferrer, Romelia, additional, Steyn, Stefanus J., additional, Webb, Damien, additional, Zhang, Lei, additional, and Grimwood, Sarah, additional

Published
2016
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7. Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy

Author

Diggle, Christine P., primary, Sukoff Rizzo, Stacey J., additional, Popiolek, Michael, additional, Hinttala, Reetta, additional, Schülke, Jan-Philip, additional, Kurian, Manju A., additional, Carr, Ian M., additional, Markham, Alexander F., additional, Bonthron, David T., additional, Watson, Christopher, additional, Sharif, Saghira Malik, additional, Reinhart, Veronica, additional, James, Larry C., additional, Vanase-Frawley, Michelle A., additional, Charych, Erik, additional, Allen, Melanie, additional, Harms, John, additional, Schmidt, Christopher J., additional, Ng, Joanne, additional, Pysden, Karen, additional, Strick, Christine, additional, Vieira, Päivi, additional, Mankinen, Katariina, additional, Kokkonen, Hannaleena, additional, Kallioinen, Matti, additional, Sormunen, Raija, additional, Rinne, Juha O., additional, Johansson, Jarkko, additional, Alakurtti, Kati, additional, Huilaja, Laura, additional, Hurskainen, Tiina, additional, Tasanen, Kaisa, additional, Anttila, Eija, additional, Marques, Tiago Reis, additional, Howes, Oliver, additional, Politis, Marius, additional, Fahiminiya, Somayyeh, additional, Nguyen, Khanh Q., additional, Majewski, Jacek, additional, Uusimaa, Johanna, additional, Sheridan, Eamonn, additional, and Brandon, Nicholas J., additional

Published
2016
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8. Design and optimization of selective azaindole amide M 1 positive allosteric modulators

Author

Davoren, Jennifer E., primary, O’Neil, Steven V., additional, Anderson, Dennis P., additional, Brodney, Michael A., additional, Chenard, Lois, additional, Dlugolenski, Keith, additional, Edgerton, Jeremy R., additional, Green, Michael, additional, Garnsey, Michelle, additional, Grimwood, Sarah, additional, Harris, Anthony R., additional, Kauffman, Gregory W., additional, LaChapelle, Erik, additional, Lazzaro, John T., additional, Lee, Che-Wah, additional, Lotarski, Susan M., additional, Nason, Deane M., additional, Obach, R. Scott, additional, Reinhart, Veronica, additional, Salomon-Ferrer, Romelia, additional, Steyn, Stefanus J., additional, Webb, Damien, additional, Yan, Jiangli, additional, and Zhang, Lei, additional

Published
2016
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13. Inositol Phosphate Accumulation in Vivo Provides a Measure of Muscarinic M1Receptor Activation

Author

Popiolek, Michael, Nguyen, David P., Reinhart, Veronica, Edgerton, Jeremy R., Harms, John, Lotarski, Susan M., Steyn, Stefanus J., Davoren, Jennifer E., and Grimwood, Sarah

Abstract

The rationale for using M1selective muscarinic acetylcholine receptor activators for the treatment of cognitive impairment associated with psychiatric and neurodegenerative disease is well-established in the literature. Here, we investigate measurement of inositol phosphate accumulation, an end point immediately downstream of the M1muscarinic acetylcholine receptor signaling cascade, as an in vivo biochemical readout for M1muscarinic acetylcholine receptor activation. Five brain penetrant M1-subtype selective activators from three structurally distinct chemical series were pharmacologically profiled for functional activity in vitro using recombinant cell calcium mobilization and inositol phosphate assays, and a native tissue hippocampal slice electrophysiology assay, to show that all five compounds presented a positive allosteric modulator agonist profile, within a narrow range of potencies. In vivo characterization using an amphetamine-stimulated locomotor activity behavioral assay and the inositol phosphate accumulation biochemical assay demonstrated that the latter has utility for assessing functional potency of M1activators. Efficacy measured by inositol phosphate accumulation in mouse striatum compared favorably to efficacy in reversing amphetamine-induced locomotor activity, suggesting that the inositol phosphate accumulation assay has utility for the evaluation of M1muscarinic acetylcholine receptor activators in vivo. The benefits of this in vivo biochemical approach include a wide response window, interrogation of specific brain circuit activation, an ability to model responses in the context of brain exposure, an ability to rank order compounds based on in vivo efficacy, and minimization of animal use.

Published
2016
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14. Inositol Phosphate Accumulation in Vivo Provides a Measure of Muscarinic M 1 Receptor Activation.

Author

Popiolek M, Nguyen DP, Reinhart V, Edgerton JR, Harms J, Lotarski SM, Steyn SJ, Davoren JE, and Grimwood S

Subjects
Amphetamine pharmacology, Animals, Brain metabolism, Brain physiology, CHO Cells, Corpus Striatum drug effects, Corpus Striatum metabolism, Corpus Striatum physiology, Cricetinae, Cricetulus, Dopamine Agents pharmacology, Dose-Response Relationship, Drug, Electrophysiological Phenomena drug effects, Hippocampus drug effects, Hippocampus metabolism, Hippocampus physiology, Humans, Male, Mice, Motor Activity drug effects, Muscarinic Agonists classification, Rats, Sprague-Dawley, Receptor, Muscarinic M1 metabolism, Brain drug effects, Calcium metabolism, Inositol Phosphates metabolism, Muscarinic Agonists pharmacology, Receptor, Muscarinic M1 agonists
Abstract

The rationale for using M 1 selective muscarinic acetylcholine receptor activators for the treatment of cognitive impairment associated with psychiatric and neurodegenerative disease is well-established in the literature. Here, we investigate measurement of inositol phosphate accumulation, an end point immediately downstream of the M 1 muscarinic acetylcholine receptor signaling cascade, as an in vivo biochemical readout for M 1 muscarinic acetylcholine receptor activation. Five brain penetrant M 1 -subtype selective activators from three structurally distinct chemical series were pharmacologically profiled for functional activity in vitro using recombinant cell calcium mobilization and inositol phosphate assays, and a native tissue hippocampal slice electrophysiology assay, to show that all five compounds presented a positive allosteric modulator agonist profile, within a narrow range of potencies. In vivo characterization using an amphetamine-stimulated locomotor activity behavioral assay and the inositol phosphate accumulation biochemical assay demonstrated that the latter has utility for assessing functional potency of M 1 activators. Efficacy measured by inositol phosphate accumulation in mouse striatum compared favorably to efficacy in reversing amphetamine-induced locomotor activity, suggesting that the inositol phosphate accumulation assay has utility for the evaluation of M 1 muscarinic acetylcholine receptor activators in vivo. The benefits of this in vivo biochemical approach include a wide response window, interrogation of specific brain circuit activation, an ability to model responses in the context of brain exposure, an ability to rank order compounds based on in vivo efficacy, and minimization of animal use.

Published
2016
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