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You searched for +publisher:"University of Kansas" +contributor:("Moise, Alex"). Showing records 1 – 3 of 3 total matches.

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1. Xu, Chenshu. REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR.

Degree: PhD, Pharmacology & Toxicology, 2011, University of Kansas

Liver-enriched nuclear receptor (NR) proteins regulate the expression and activity of several pivotal hepatic biochemical pathways including the uptake, metabolism and excretion of cholesterol, bile acids, glucose, and xenobiotic compounds from the body. The pregnane x receptor (PXR, NR1I2) was first identified in 1998 as a member of the NR superfamily. Over the past decade, it has been well established that PXR functions as a master-regulator of xenobiotic- and drug-inducible expression and activity of numerous genes that encode key members of the phase I and phase II metabolic enzymes, as well as several membrane transporter proteins. In this way, activation of PXR serves as the principal defense mechanism defending the body from toxic insult. Similarly, the PXR protein also forms the molecular basis of an important class of drug-drug interactions in the clinical setting. Moreover, ligand-activated PXR negatively regulates inflammatory processes in both liver and intestine. An integrated model is emerging to reveal a key role for the post-translational modification of PXR in the selective suppression of gene expression, and is opening the door to the study of completely new modes of PXR-mediated gene regulation. This dissertation contributes mainly to two key areas of PXR research: (1) Identification a novel PXR target gene- carboxylesterase 6 (Ces6); (2) a study of the SUMOylation and ubiquitination of PXR protein. The results presented in this dissertation were primarily obtained from mouse and cell-culture systems. Data presented here reveal that activation of the inflammatory response modulates the SUMOylation and ubiquitination status of ligand-bound PXR protein. The SUMOylation and ubiquitination of the PXR protein functions to feedback-repress the inflammatory and xenobiotic responses, respectively. Taken together, the data represent a likely mechanism and provides initial molecular details for the connection between the PXR signaling pathway and inflammation. Studies on post-translational modification of PXR indicate how this protein is converted from a positive regulator in drug metabolism into a transcriptional repressor in inflammatory response. Finally, detailed protocols for purification of mammalian proteins necessary to perform in vitro SUMOylation reactions are presented. Taken together, the work presented in this dissertation contributes to understanding the interface between PXR, drug metabolism, and inflammation, which is expected to produce new opportunities for the development of novel therapeutic strategies. Advisors/Committee Members: Staudinger, Jeff L. (advisor), Dobrowsky, Rick T (cmtemember), Shi, Honglian (cmtemember), Moise, Alex (cmtemember), Lundquist, Erik A. (cmtemember).

Subjects/Keywords: Pharmacology; Toxicology; Carboxylesterase; Constitutive androstane receptor; Inflammation; Pregnane x receptor; Sumoylation

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APA (6th Edition):

Xu, C. (2011). REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/9708

Chicago Manual of Style (16th Edition):

Xu, Chenshu. “REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR.” 2011. Doctoral Dissertation, University of Kansas. Accessed January 18, 2021. http://hdl.handle.net/1808/9708.

MLA Handbook (7th Edition):

Xu, Chenshu. “REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR.” 2011. Web. 18 Jan 2021.

Vancouver:

Xu C. REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR. [Internet] [Doctoral dissertation]. University of Kansas; 2011. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1808/9708.

Council of Science Editors:

Xu C. REGULATION OF DRUG METABOLISM AND INFLAMMATION BY PREGNANE X RECEPTOR. [Doctoral Dissertation]. University of Kansas; 2011. Available from: http://hdl.handle.net/1808/9708

2. Li, Chengyuan. Small Molecule Hsp90 Modulator and Neuregulin-induced Peripheral Demyelination.

Degree: PhD, Pharmacology & Toxicology, 2012, University of Kansas

Abstract Modulating molecular chaperones is emerging as an attractive approach to treat neurodegenerative diseases associated with protein aggregation, diabetic peripheral neuropathy (DPN) and possibly, demyelinating neuropathies. KU-32 is a small molecule inhibitor of heat shock protein 90 (Hsp90) and reverses sensory deficits associated with myelinated fiber dysfunction in DPN. Additionally, KU-32 prevented the loss of myelinated internodes induced by treating myelinated Schwann cell-dorsal root ganglia sensory neuron co-cultures with neuregulin-1 Type 1 (NRG1). Since KU-32 decreased NRG1-induced demyelination in an Hsp70-dependent manner, the goal of the current study was to clarify how Hsp70 may be mechanistically linked to preventing demyelination. The activation of p42/p44 MAPK and induction of the transcription factor c-jun function as negative regulators of myelination. NRG1 activated MAPK, induced c-jun expression and promoted a loss of myelin segments in DRG explants isolated from both wild type and Hsp70 KO mice. Although KU-32 did not block the activation of MAPK, it blocked c-jun induction and protected against a loss of myelinated segments in wildtype (WT) mice. KU-32 did not prevent the NRG1-dependent induction of c-jun and loss of myelin segments in explants from Hsp70 KO mice. Over-expression of Hsp70 in myelinated DRG explants prepared from WT or Hsp70 KO mice was sufficient to block the induction of c-jun and the loss of myelin segments induced by NRG1. Lastly, inhibiting the proteasome prevented KU-32 from decreasing c-jun levels. Collectively, these data support that Hsp70 induction is sufficient to prevent NRG1-induced demyelination by enhancing the proteasomal degradation of c-jun. Advisors/Committee Members: Dobrowsky, Rick T (advisor), Muma, Nancy (cmtemember), Moise, Alex R (cmtemember), Lundquist, Erik A. (cmtemember), Neufeld, Kristi L (cmtemember).

Subjects/Keywords: Pharmacology; Neurosciences; Medicine; Demyelination; Diabetic peripheral neuropathy; Hsp70; Hsp90 inhibitor; Neuregulin; Pharmacological treatment

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Li, C. (2012). Small Molecule Hsp90 Modulator and Neuregulin-induced Peripheral Demyelination. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/13029

Chicago Manual of Style (16th Edition):

Li, Chengyuan. “Small Molecule Hsp90 Modulator and Neuregulin-induced Peripheral Demyelination.” 2012. Doctoral Dissertation, University of Kansas. Accessed January 18, 2021. http://hdl.handle.net/1808/13029.

MLA Handbook (7th Edition):

Li, Chengyuan. “Small Molecule Hsp90 Modulator and Neuregulin-induced Peripheral Demyelination.” 2012. Web. 18 Jan 2021.

Vancouver:

Li C. Small Molecule Hsp90 Modulator and Neuregulin-induced Peripheral Demyelination. [Internet] [Doctoral dissertation]. University of Kansas; 2012. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1808/13029.

Council of Science Editors:

Li C. Small Molecule Hsp90 Modulator and Neuregulin-induced Peripheral Demyelination. [Doctoral Dissertation]. University of Kansas; 2012. Available from: http://hdl.handle.net/1808/13029

3. Franklin, Jade M. Cannabinoid Regulation of Serotonin 2A (5-HT2A) Receptor Signaling.

Degree: PhD, Pharmacology & Toxicology, 2013, University of Kansas

Accumulating evidence indicates that sustained cannabinoid agonist exposure may precipitate the onset of some neuropsychiatric disorders that are associated with dysfunction of serotonin 2A (5-HT2A ) receptor neurotransmission in the brain. Recent behavioral evidence suggests that non-selective cannabinoid agonists can regulate 5-HT2A receptor signaling in the brain. However, the molecular mechanisms of this cannabinoid-induced change in 5-HT2A receptor signaling are unknown. Here we present experimental evidence that repeated treatment with a non-selective cannabinoid agonist, CP55940, can enhance 5-HT2A receptor activity and expression in the rodent prefrontal cortex (PFCx) and two neuronal cell culture models, CLU13 and A1A1v cells. Cannabinoids mediate many of their physiological effects through two cannabinoid receptors, cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2 ), which are expressed in the brain. Our evidence indicates that CB2 receptors would mediate this phenomenon because cannabinoid-induced upregulation and enhanced activity of 5-HT2A receptors was: (1) induced by selective CB2 receptor but not selective CB1 receptor agonists and (2) inhibited by CB2 but not CB1 shRNA lentiviral particles in neuronal cells. CB2 receptors are positively coupled to the Extracellular Regulated Kinase 1/2 (ERK1/2) signaling cascade which has been shown to regulate transcription factors, such as cyclic AMP response binding protein (CREB) and activator protein 1 (AP-1), which have consensus sequences in the rat 5-HT2A receptor promoter. Interestingly, we found that cannabinoid-induced upregulation of 5-HT2A receptors was inhibited by ERK1/2 inhibitors and AP-1, but not CREB, inhibitor. Studies show that G-protein receptor kinases (GRKs), such as GRK5, can phosphorylate G-protein coupled receptors (GPCRs) to regulate the formation of the Beta ( β )-Arrestin 2/ERK scaffolding complex that can modulate the long term activation of ERK1/2 signaling. Indeed, we found that â-Arrestin2 shRNA lentiviral treatment prevents cannabinoid-induced upregulation of 5-HT2A receptor and significantly reduces cannabinoid activation of ERK1/2 signaling. Moreover, GRK5 shRNA lentiviral particle treatment inhibits cannabinoid-induced: (1) enhanced CB2 receptor phosphorylation (2) enhanced co-immunopreciptiation of β -Arrestin 2 and ERK1/2 and (3) upregulation and enhanced activity of 5-HT2A receptors. The enhanced function of 5-HT2A receptors could also involve cannabinoid-induced enhanced interaction between 5-HT2A and dopamine D2 (D2) receptors. We found that Sprague-Dawley rats treated with a non-selective cannabinoid receptor agonist (CP55940) showed enhanced co-immunoprecipitation of 5-HT2A and D2 receptors. Formation of the functional 5-HT2A and D2 receptor heteromer in the PFCx is suggested to contribute to the pathophysiology of neuropsychiatric disorders such as schizophrenia. Furthermore, enhanced activity of cortical 5-HT2A receptors is associated with several physiological functions and neuropsychiatric disorders such as stress… Advisors/Committee Members: Carrasco, Gonzalo A (advisor), Muma, Nancy (cmtemember), Shi, Honglian (cmtemember), Moise, Alex (cmtemember), Richter, Mark L (cmtemember).

Subjects/Keywords: Pharmacology; Molecular biology; Neurosciences; 5-HT2A receptor; Cannabinoid; Cannabinoid receptor; Erk1/2; Grk5; Prefrontal cortex

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Franklin, J. M. (2013). Cannabinoid Regulation of Serotonin 2A (5-HT2A) Receptor Signaling. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/13014

Chicago Manual of Style (16th Edition):

Franklin, Jade M. “Cannabinoid Regulation of Serotonin 2A (5-HT2A) Receptor Signaling.” 2013. Doctoral Dissertation, University of Kansas. Accessed January 18, 2021. http://hdl.handle.net/1808/13014.

MLA Handbook (7th Edition):

Franklin, Jade M. “Cannabinoid Regulation of Serotonin 2A (5-HT2A) Receptor Signaling.” 2013. Web. 18 Jan 2021.

Vancouver:

Franklin JM. Cannabinoid Regulation of Serotonin 2A (5-HT2A) Receptor Signaling. [Internet] [Doctoral dissertation]. University of Kansas; 2013. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1808/13014.

Council of Science Editors:

Franklin JM. Cannabinoid Regulation of Serotonin 2A (5-HT2A) Receptor Signaling. [Doctoral Dissertation]. University of Kansas; 2013. Available from: http://hdl.handle.net/1808/13014

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