+publisher:"University of Kansas" +contributor:("Hagenbuch, Bruno")

University of Kansas

1. Mickey, Kristen Elizabeth. Arsenic Toxicity and Altered Mitochondrial Bioenergetics in Response to Oxidative Stress.

Degree: MS, Pharmacology, Toxicology & Therapeutics, 2015, University of Kansas

URL: http://hdl.handle.net/1808/19447

► Environmental exposure to arsenic is a worldwide health concern which is linked to a number of diseases. Areas with arsenic levels above the current safe… (more)

Subjects/Keywords: Toxicology; Cellular biology; Molecular biology; Arsenic; Mitochondria; Oxidative Stress

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APA (6^th Edition):

Mickey, K. E. (2015). Arsenic Toxicity and Altered Mitochondrial Bioenergetics in Response to Oxidative Stress. (Masters Thesis). University of Kansas. Retrieved from http://hdl.handle.net/1808/19447

Chicago Manual of Style (16^th Edition):

Mickey, Kristen Elizabeth. “Arsenic Toxicity and Altered Mitochondrial Bioenergetics in Response to Oxidative Stress.” 2015. Masters Thesis, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/19447.

MLA Handbook (7^th Edition):

Mickey, Kristen Elizabeth. “Arsenic Toxicity and Altered Mitochondrial Bioenergetics in Response to Oxidative Stress.” 2015. Web. 19 Jan 2021.

Vancouver:

Mickey KE. Arsenic Toxicity and Altered Mitochondrial Bioenergetics in Response to Oxidative Stress. [Internet] [Masters thesis]. University of Kansas; 2015. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/19447.

Council of Science Editors:

Mickey KE. Arsenic Toxicity and Altered Mitochondrial Bioenergetics in Response to Oxidative Stress. [Masters Thesis]. University of Kansas; 2015. Available from: http://hdl.handle.net/1808/19447

University of Kansas

2. Polireddy, Kishore. Identifying Novel Inhibitors of Epithelial to Mesenchymal Transition (EMT) for Targeting Pancreatic Cancer Metastasis and Cancer Stem Cells.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2015, University of Kansas

URL: http://hdl.handle.net/1808/21926

► Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, and it is expected to become the second-leading cause of cancer-related… (more)

▼ Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, and it is expected to become the second-leading cause of cancer-related death by 2030. Currently, there are no early detection tests and most patients with localized disease have no recognizable symptoms. As a result, more than half of the patients with this disease are diagnosed at a stage where metastases have developed, for whom the overall 5-year survival is only 2%. Moreover, these tumors are highly enriched with a cancer stem cell (CSC) population (~1%), which is highly resistant to chemotherapeutic drugs, and therefore escapes chemotherapy and promotes tumor recurrence. Recent evidence suggests that epithelial to mesenchymal transition (EMT) is associated with metastasis, generation of CSCs, and treatment resistance in solid tumors including pancreatic cancer. Therefore, compounds inhibiting EMT hold the potential to reverse drug-resistance or inhibit metastasis and CSCs, and therefore could provide better treatment outcome for patients with pancreatic cancer. The overall goal of this dissertation is to investigate novel EMT inhibitors for targeting pancreatic cancer metastasis and CSCs. First we demonstrated in preclinical models that treatment with pharmacological doses of ascorbate resulted in inhibition of EMT, metastasis and CSCs. In addition, ascorbate decreased the expression of HDAC6, and inhibited activity of Sirt-2 by depleting NAD+ levels resulting in robustly increased α-tubulin acetylation in pancreatic cancer cells. Ascorbate mediated tubulin acetylation promoted α-tubulin polymerization and stabilization, mimicking the cellular outcomes of paclitaxel to inhibit cancer cell metastasis. Next, we investigated novel derivatives of the histone deacetylase (HDAC) inhibitors SAHA and MS-275, which are known EMT inhibitors. In an effort to increase efficacy and reduce toxicities of the HDAC inhibitors, we found that the novel synthetic compounds St-1 and St-3 potently inhibited pancreatic cancer cell proliferation and CSCs. St-1 has exhibited similar potency in HDAC inhibition compared to the parent compounds (SAHA and MS-275). Surprisingly, St-3 acted via totally different mechanisms from SAHA and MS-275. St-3 exhibited anti-tumor effects by blocking the interaction of human antigen R (HuR) with its target mRNAs. Finally, we established and performed a high throughput screening approach to identify inhibitiors of cancer cell EMT. 1-(benzylsulfonyl) indoline (BSI) was found to be a novel EMT inhibitor. BSI significantly inhibited pancreatic cancer cell migration invasion and CSCs. To enhance the efficacy of BSI, several analogues of BSI were tested for their activities on EMT and CSC inhibition. However, BSI analogues failed to show superior anti-migration or anti-CSC activities compare to BSI. In conclusion, this dissertation resulted in the identification of several novel EMT inhibitors, which can be tested further in preclinical studies for their anti-tumor efficacy. Advisors/Committee Members: Chen, Qi (advisor), Ding, Wen-Xing (cmtemember), Hagenbuch, Bruno (cmtemember), Kasturi, Partha (cmtemember), Anant, Shrikant (cmtemember).

Subjects/Keywords: Oncology; Biology; Cancer stem cells; EMT; Pancreatic cancer

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APA (6^th Edition):

Polireddy, K. (2015). Identifying Novel Inhibitors of Epithelial to Mesenchymal Transition (EMT) for Targeting Pancreatic Cancer Metastasis and Cancer Stem Cells. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/21926

Chicago Manual of Style (16^th Edition):

Polireddy, Kishore. “Identifying Novel Inhibitors of Epithelial to Mesenchymal Transition (EMT) for Targeting Pancreatic Cancer Metastasis and Cancer Stem Cells.” 2015. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/21926.

MLA Handbook (7^th Edition):

Polireddy, Kishore. “Identifying Novel Inhibitors of Epithelial to Mesenchymal Transition (EMT) for Targeting Pancreatic Cancer Metastasis and Cancer Stem Cells.” 2015. Web. 19 Jan 2021.

Vancouver:

Polireddy K. Identifying Novel Inhibitors of Epithelial to Mesenchymal Transition (EMT) for Targeting Pancreatic Cancer Metastasis and Cancer Stem Cells. [Internet] [Doctoral dissertation]. University of Kansas; 2015. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/21926.

Council of Science Editors:

Polireddy K. Identifying Novel Inhibitors of Epithelial to Mesenchymal Transition (EMT) for Targeting Pancreatic Cancer Metastasis and Cancer Stem Cells. [Doctoral Dissertation]. University of Kansas; 2015. Available from: http://hdl.handle.net/1808/21926

University of Kansas

3. Zhao, Wen. Identification and characterization of the transporters involved in the disposition of perfluoroalkyl substances.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2016, University of Kansas

URL: http://hdl.handle.net/1808/24802

► Perfluoroalkyl substances (PFASs), including perfluoroalkyl carboxylates (PFCAs) and perfluoroalkyl sulfonates (PFSAs), are persistent amphiphilic chemicals many of which are distributed ubiquitously in the environment and… (more)

▼ Perfluoroalkyl substances (PFASs), including perfluoroalkyl carboxylates (PFCAs) and perfluoroalkyl sulfonates (PFSAs), are persistent amphiphilic chemicals many of which are distributed ubiquitously in the environment and can be frequently detected in human serum. High doses of certain PFAS cause toxicities in animal models. Renal clearance and hepatic accumulation of PFASs can vary among different species, between genders in the same species and are also influenced by the carbon chain length of the individual PFCAs. In general, PFASs with shorter-chain length are eliminated more efficiently through the kidney whereas the longer-chain length PFASs tend to accumulate in liver. Although there were extensive studies published over the past decade regarding toxicities of PFASs in animal models and potential health risks in humans, the molecular mechanisms responsible for PFAS’s disposition, such as the roles of specific transporters involved, have not been clearly addressed. Absorption, distribution and elimination of certain xenobiotics are largely influenced by transporters and recently published studies demonstrate that also PFCAs are substrates for several transporters. In order to further delineate the pharmacokinetic properties of the disposition of PFASs, the involvement of drug transporters expressed in liver, intestine and kidney was examined. In the first specific aim, I evaluated the hypothesis that drug transporters in the enterohepatic circulation contribute to the liver accumulation and long half-lives of long chain PFASs. To address this aim, uptake studies with perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) using cells expressing liver transporters NTCP or OATPs as well as intestinal transporters ASBT, OATPs or OSTα/β were performed. The results demonstrated that human and rat NTCP, human OATP1B1, OATP1B3, OATP2B1, OSTα/β and rat OATP1A1, OATP1B2, OATP2B1, OATP1A5 can transport all three PFSAs, whereas, human ASBT can only transport PFOS. In addition, inhibition studies with human MRP2, BCRP and BSEP containing Sf9 vesicles suggested that these efflux transporters might be involved in the canalicular secretion of PFHxS and/or PFOS in the liver. In the second specific aim, I evaluated the hypothesis that the differences of renal clearance of PFASs among different species and genders are due to the differences of specific transporters expressed in the kidney. To address this aim, rat renal transporters OAT1, OAT3 and OATP1A1 were examined for the transport of PFBS, PFHxS and PFOS. The results show that the three PFSAs are substrates of rat OAT1, OAT3 and OATP1A1. In summary, this dissertation reveals that 1) drug transporters expressed in the liver and the intestine and involved in the enterohepatic circulation of bile acids contribute to the long halflives and the hepatic accumulation of PFHxS and PFOS in humans; 2) drug transporters in the liver, the intestine and the kidney contribute to species-, gender- and chain length-dependent elimination of… Advisors/Committee Members: Hagenbuch, Bruno A (advisor), Apte, Udayan (cmtemember), Pritchard, Michele (cmtemember), Reed, Gregory (cmtemember), Blanco, Gustavo (cmtemember).

Subjects/Keywords: Pharmacology; Toxicology; Drug transporters; Enterohepatic circulation; Perfluoroalkyl substances; PFBS; PFHxS; PFOS

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

APA (6^th Edition):

Zhao, W. (2016). Identification and characterization of the transporters involved in the disposition of perfluoroalkyl substances. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/24802

Chicago Manual of Style (16^th Edition):

Zhao, Wen. “Identification and characterization of the transporters involved in the disposition of perfluoroalkyl substances.” 2016. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/24802.

MLA Handbook (7^th Edition):

Zhao, Wen. “Identification and characterization of the transporters involved in the disposition of perfluoroalkyl substances.” 2016. Web. 19 Jan 2021.

Vancouver:

Zhao W. Identification and characterization of the transporters involved in the disposition of perfluoroalkyl substances. [Internet] [Doctoral dissertation]. University of Kansas; 2016. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/24802.

Council of Science Editors:

Zhao W. Identification and characterization of the transporters involved in the disposition of perfluoroalkyl substances. [Doctoral Dissertation]. University of Kansas; 2016. Available from: http://hdl.handle.net/1808/24802

University of Kansas

4. Bishop, Stephanie Cara. Development of Novel Fluorescence and NMR Reagents for Monitoring Protein-Protein Interactions Between Survivin and Its Protein Binding Partners.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2015, University of Kansas

URL: http://hdl.handle.net/1808/19468

► Inhibition of protein-protein interactions is a promising therapeutic strategy for targeting non-enzymatic proteins. One strategy to inhibit protein-protein interactions is to design inhibitors specifically toward… (more)

▼ Inhibition of protein-protein interactions is a promising therapeutic strategy for targeting non-enzymatic proteins. One strategy to inhibit protein-protein interactions is to design inhibitors specifically toward the protein-protein interaction interface. To achieve this objective using structure-aided design, knowledge of the structure of the interface of the protein-protein interaction is needed. Augmenting the utility of NMR to determine the structure of larger proteins, and of protein complexes, than is currently achieved with conventional approaches, expands structure-aided design and to evaluate protein-protein interactions for target proteins relevant to human disease such as cancer. A second approach to bring new therapies to the clinic is to identify lead molecules using high-throughput screening. High-throughput screening (HTS) offers the potential to more rapidly and less expensively identify promising molecules that may inhibit a specific protein-protein interaction. To improve efforts at structure-aided design, we hypothesize that we can expand the utility of fluorescence- and NMR-based approaches to monitor protein-protein interactions by incorporating fluorescent or paramagnetic labels, site-specifically, into a protein of interest. This technology will provide much more structural detail regarding the binding site of a candidate small molecule protein-protein interaction inhibitor. This structural information can then be used in downstream medicinal chemistry efforts to improve inhibitor affinity and specificity. Additionally, site-specific fluorescent and paramagnetic labels can be used in sensitive HTS assays for protein-protein interaction inhibitors. The lanthanide series of elements, which possess intriguing spectroscopic and paramagnetic properties, was chosen to accomplish these efforts. Lanthanides exhibit luminescence and have excitation and emission maxima unique from biological fluorophores, broad Stokes shifts, and narrow emission bands. In the context of NMR, some lanthanides impart long-range perturbations in the form of paramagnetic relaxation enhancements, pseudocontact chemical shifts, and residual dipolar couplings, which are used to facilitate protein structure determination. Site-specific labeling of the protein of interest was achieved using site-directed mutagenesis followed by incorporation of the unnatural amino acid para-azidophenylalanine (paF). Synthesis of the small-molecule lanthanide chelator amenable to copper-free click chemistry-mediated incorporation is described herein. To improve efforts at identification of candidate protein-protein interaction inhibitors, we hypothesized that a high-throughput fluorescence polarization screening assay could be established. Inhibitors identified in this assay would be further characterized using the lanthanide labeled Survivin protein. A recently-identified cancer target, the Survivin protein, was evaluated using the methodologies described herein. The results demonstrate we were able to fluorescently label the Survivin protein… Advisors/Committee Members: Lampe, Jed N (advisor), Chen, Qi (cmtemember), Fisher, Mark (cmtemember), Hagenbuch, Bruno (cmtemember), Reed, Greg (cmtemember).

Subjects/Keywords: Pharmacology; Biochemistry; Organic chemistry; Copper-free click chemistry; Fluorescence; Lanthanide chelation; Nuclear Magnetic Resonance; Paramagnetism; Unnatural Amino Acid Incorporation

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

APA (6^th Edition):

Bishop, S. C. (2015). Development of Novel Fluorescence and NMR Reagents for Monitoring Protein-Protein Interactions Between Survivin and Its Protein Binding Partners. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/19468

Chicago Manual of Style (16^th Edition):

Bishop, Stephanie Cara. “Development of Novel Fluorescence and NMR Reagents for Monitoring Protein-Protein Interactions Between Survivin and Its Protein Binding Partners.” 2015. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/19468.

MLA Handbook (7^th Edition):

Bishop, Stephanie Cara. “Development of Novel Fluorescence and NMR Reagents for Monitoring Protein-Protein Interactions Between Survivin and Its Protein Binding Partners.” 2015. Web. 19 Jan 2021.

Vancouver:

Bishop SC. Development of Novel Fluorescence and NMR Reagents for Monitoring Protein-Protein Interactions Between Survivin and Its Protein Binding Partners. [Internet] [Doctoral dissertation]. University of Kansas; 2015. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/19468.

Council of Science Editors:

Bishop SC. Development of Novel Fluorescence and NMR Reagents for Monitoring Protein-Protein Interactions Between Survivin and Its Protein Binding Partners. [Doctoral Dissertation]. University of Kansas; 2015. Available from: http://hdl.handle.net/1808/19468

University of Kansas

5. Zhang, Youcai. CHARACTERIZATION OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1A1 (OATP1A1) IN THE BILE ACID HOMEOSTASIS OF MICE.

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

URL: http://hdl.handle.net/1808/7930

► Organic anion transporting polypeptides (human: OATPs; all other species: Oatps; gene symbol: SLCO/Slco) are sodium-independent transport systems that mediate the transmembrane transport of a wide… (more)

▼ Organic anion transporting polypeptides (human: OATPs; all other species: Oatps; gene symbol: SLCO/Slco) are sodium-independent transport systems that mediate the transmembrane transport of a wide range of amphipathic endogenous and exogenous organic compounds. In mice, Oatp1a1, 1a4, and 1b2 are thought to account for the bulk of Na-independent bile acid (BA) uptake into liver during normal physiological conditions. The overall goal of this dissertation has focused on characterization of the in vivo role of mouse Oatp1a1 in BA homeostasis by using Oatp1a1-null mice. To achieve this overall goal, three specific aims were examined in the present dissertation. In the first specific aim, a simple and sensitive UPLC-MS/MS method was established and validated for the simultaneous analysis of various BAs, and applied to investigate liver BA content in C57BL/6 mice fed 1% cholic acid (CA), 0.3% deoxycholic acid (DCA), 0.3% chenodeoxycholic acid (CDCA), 0.3% lithocholic acid (LCA), 3% ursodeoxycholic acid (UDCA), or 2% cholestyramine (resin). The purpose of this study was to understand the BA metabolic pathways in mice by using this newly developed BA-quantification method, and thus to provide tools and knowledge for the future study in Oatp1a1-null mice. Gender differences in liver BA composition were observed after feeding CA, DCA, CDCA, and LCA, but were not prominent after feeding UDCA. Sulfation of CA and CDCA was found at the 7-OH position, and increased by feeding CA or CDCA more in male than female mice. In contrast, sulfation of LCA and taurolithocholic acid (TLCA) was female predominant, and increased by feeding UDCA and LCA. The metabolic pathways of each BA in vivo are proposed, and can be used to interpret BA-mediated gene regulation and hepatotoxicity. In the second specific aim, the hypothesis that Oatp1a1 is important in transporting unconjugated BAs was evaluated. The purpose of this study was to determine whether knockout of Oatp1a1 will alter BA metabolism in mice. To address this aim, the concentrations of individual BAs in serum, liver, and bile were compared between WT and Oatp1a1-null mice. The gender-divergent expression of Oatp1a1 was considered in the efforts to identify the endogenous BA substrates for Oatp1a1. In addition, DCA feeding and pharmacokinetic studies were conducted in WT and Oatp1a1-null mice to investigate the role of Oatp1a1 in the disposition of DCA. Data from this study show a critical role of Oatp1a1 in DCA metabolism of mice. Oatp1a1 in mouse liver does not appear to transport DCA, because knockout of Oatp1a1 does not prevent hepatic uptake and hepatotoxicity of DCA. Instead, knockout of Oatp1a1 increases the intestinal permeability and thus increases intestinal absorption of DCA. In addition, Knockout of Oatp1a1 markedly alters the composition and amount of intestinal bacteria. The alterations of intestinal bacteria in Oatp1a1-null mice result in marked changes of BA composition in the intestinal contents and feces, but have no effect on the total fecal BA excretion, due to the… Advisors/Committee Members: Klaassen, Curtis D. (advisor), Klaassen, Curtis D. (cmtemember), Guo, Grace (cmtemember), Hagenbuch, Bruno (cmtemember), Krishnamurthy, Partha (cmtemember), Andrews, Glen K. (cmtemember).

Subjects/Keywords: Toxicology; Bile acids; Cholestasis; Intestinal bacteria; Organic anion transporting polypeptide

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

APA (6^th Edition):

Zhang, Y. (2011). CHARACTERIZATION OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1A1 (OATP1A1) IN THE BILE ACID HOMEOSTASIS OF MICE. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/7930

Chicago Manual of Style (16^th Edition):

Zhang, Youcai. “CHARACTERIZATION OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1A1 (OATP1A1) IN THE BILE ACID HOMEOSTASIS OF MICE.” 2011. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/7930.

MLA Handbook (7^th Edition):

Zhang, Youcai. “CHARACTERIZATION OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1A1 (OATP1A1) IN THE BILE ACID HOMEOSTASIS OF MICE.” 2011. Web. 19 Jan 2021.

Vancouver:

Zhang Y. CHARACTERIZATION OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1A1 (OATP1A1) IN THE BILE ACID HOMEOSTASIS OF MICE. [Internet] [Doctoral dissertation]. University of Kansas; 2011. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/7930.

Council of Science Editors:

Zhang Y. CHARACTERIZATION OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1A1 (OATP1A1) IN THE BILE ACID HOMEOSTASIS OF MICE. [Doctoral Dissertation]. University of Kansas; 2011. Available from: http://hdl.handle.net/1808/7930

University of Kansas

6. Selwyn Samraj, Felcy Pavithra. Alterations in bile acid homeostasis and drug metabolism in germ-free mice.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2014, University of Kansas

URL: http://hdl.handle.net/1808/23957

► "We may be born 100% human but will die 90% bacterial – a truly complex organism!" (Goodacre, 2007). This statement reflects the fact that there are… (more)

▼ "We may be born 100% human but will die 90% bacterial – a truly complex organism!" (Goodacre, 2007). This statement reflects the fact that there are 10 times more bacterial cells in the human body compared to the number of human cells, and there are 100 times more genes in the human microbiome compared to the number of genes in the human genome. Gut bacteria and host communicate with each other and collectively determine many aspects of host physiology such as bile acid (BA) and drug metabolism. Gut bacteria varies significantly between individuals and therefore, may be responsible for the inter-individual differences in BA concentrations and drug responses. There are a number of diseases such as obesity, inflammatory bowel disorder, and autism, that have been associated with an abnormal bloom in certain gut bacteria or a decrease in the diversity of gut bacteria. Therefore, modulating gut bacteria by probiotics, prebiotics, and by fecal transplantation have become viable therapeutic strategies. Alterations of gut bacteria in diseases or the therapeutic modulation of gut bacteria has the potential to alter host BA signaling and drug responses. Germ-free (GF) mice provide an excellent model system for understanding the functions of gut bacteria. The overall goal of this dissertation is to expand the understanding of the role of gut bacteria in regulating host BA homeostasis and hepatic drug metabolism. In Specific Aim 1, I determined the changes in BA homeostasis and BA signaling in GF mice. BAs are amphipathic cholesterol metabolites that are synthesized in liver and secreted into bile. Gut bacteria metabolize primary BAs to secondary BAs. The majority of BAs are reabsorbed from the intestine, effluxed into the portal vein and return to the liver. Therefore, the BA profile in the host is the result of the host hepatic enzyme activity and the gut bacterial enzyme activity. The BA profile is important because, BAs act like hormones and regulate host physiology by activating the BA receptors, namely the farnesoid X receptor (FXR) and transmembrane G-protein-coupled receptor (TGR5). The BA profiles of both male and female GF mice are markedly altered compared to conventional (CV) mice. GF mice have an increase in total BAs in all the tissue compartments analyzed and decreased total fecal excretion of BAs compared to CV mice. This could be due to slower intestinal propulsion rates and increased BA reabsorption from the intestines. The dominant BAs in GF mice are taurine conjugated α and β muricholic acids (Tα+β MCA). There is an increase in both ursodeoxycholic acid (UDCA) and MCAs and in the proportion of taurine conjugated BAs and these BAs result in a more hydrophilic BA pool in GF mice. UDCA which was previously considered to be a secondary BA that is synthesized by gut bacteria increases in GF mice. Biotransformation experiments in vitro demonstrated that UDCA can be synthesized from CDCA by enzymes present in hepatic microsomes isolated from both GF and CV mice. This explains why UDCA is increased… Advisors/Committee Members: Klaassen, Curtis D (advisor), Pazdernik, Thomas (advisor), Pazdernik, Thomas (cmtemember), Hagenbuch, Bruno (cmtemember), Blanco, Gustavo (cmtemember), Kasturi, Partha (cmtemember), Li, Tiangang (cmtemember).

Subjects/Keywords: Toxicology; Physiology; Bile acid; Drug metabolism; Germ-free mice

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

APA (6^th Edition):

Selwyn Samraj, F. P. (2014). Alterations in bile acid homeostasis and drug metabolism in germ-free mice. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/23957

Chicago Manual of Style (16^th Edition):

Selwyn Samraj, Felcy Pavithra. “Alterations in bile acid homeostasis and drug metabolism in germ-free mice.” 2014. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/23957.

MLA Handbook (7^th Edition):

Selwyn Samraj, Felcy Pavithra. “Alterations in bile acid homeostasis and drug metabolism in germ-free mice.” 2014. Web. 19 Jan 2021.

Vancouver:

Selwyn Samraj FP. Alterations in bile acid homeostasis and drug metabolism in germ-free mice. [Internet] [Doctoral dissertation]. University of Kansas; 2014. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/23957.

Council of Science Editors:

Selwyn Samraj FP. Alterations in bile acid homeostasis and drug metabolism in germ-free mice. [Doctoral Dissertation]. University of Kansas; 2014. Available from: http://hdl.handle.net/1808/23957

University of Kansas

7. Tessman, Robert Thomas. The Role of Mitochondrial ATP-Binding Cassette Transporter ABCB6 in Metabolism and Energy Balance.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2019, University of Kansas

URL: http://hdl.handle.net/1808/30121

► Abstract Obesity and the associated health risks represent a world-wide health and financial crisis. Lack of physical activity combined with excessive caloric intake are the… (more)

▼ Abstract Obesity and the associated health risks represent a world-wide health and financial crisis. Lack of physical activity combined with excessive caloric intake are the root cause of the problem. Despite the increased advocation for healthy lifestyle choices, the trend has yet to reverse and indeed, seems to be on the rise especially among pre-teens and adolescents, a constituent that had not been previously part of the obesity epidemic. Mitochondria are the “fuel-burners” of the body and like other combustion devices, become inefficient in the context of fuel surplus. Moreover, with chronic over-feeding, the physiological mechanisms that regulate energy balance become permanently dysfunctional leading to the progression of pathologies such as Type II diabetes and cardiovascular disease. Medical and scientific evidence confirms that mitochondria are integral to the responses necessary to adapt to over-nutrition. However, success in mitochondria-based therapies has been extremely limited in the context of metabolic diseases. Our knowledge of the regulation of mitochondrial function, dynamics, signaling, and transport processes in different tissues and organ systems is extremely limited and this knowledge gap is a serious impediment to progress toward targeting mitochondria for treatment of metabolic diseases. In this study, we successfully genetically manipulated the expression of mitochondrial transporter ABCB6. The physiological function of this transporter is unknown but non-functional mutations of this protein have been linked to several heritable human diseases. This study establishes that ABCB6 plays a role in the maintenance of energy homeostasis. Whole-body Abcb6 knockout adult male and female mice have increased body mass with no increases in food consumption. Increased body mass is due to increased adiposity. ABCB6 deficiency results in steatosis, glucose intolerance, insulin resistance, and lower energy expenditure. Exposure to high-fat diet exacerbates these metabolic derangements. Genetically targeting ABCB6 expression specifically in liver results in disruption of whole-body energy metabolism as well with a loss of metabolic flexibility. Loss of hepatic ABCB6 results in fragmented mitochondria while overexpression leads to mitochondrial elongation, dysregulating dynamic mitochondrial functional responses to energy status. In this liver-specific model, hepatic metabolites are significantly altered with either ABCB6 knockdown or overexpression. Metabolites that have a profound impact on energy metabolism such as bile acids, amino acids, and phospholipids were significantly altered in this model. Interestingly, we discovered that ABCB6 expression is responsive to nutrient status and circadian patterns. ABCB6 expression is upregulated in the fasted state and rapidly downregulated in response to feeding. Also, ABCB6 expression is reduced in cases of chronic over-nutrition such as, diet and genetic mouse models of obesity as well as in clinically obese humans. These findings suggest that ABCB6 acts as a… Advisors/Committee Members: Kasturi, Partha (advisor), Li, Tiangang (cmtemember), Zhu, Hao (cmtemember), Hagenbuch, Bruno (cmtemember), DiTachhio, Luciano (cmtemember), Kasturi, Partha (cmtemember).

Subjects/Keywords: Toxicology; Dynamics; Metabolism; Mitochondria; Transporter

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

APA (6^th Edition):

Tessman, R. T. (2019). The Role of Mitochondrial ATP-Binding Cassette Transporter ABCB6 in Metabolism and Energy Balance. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/30121

Chicago Manual of Style (16^th Edition):

Tessman, Robert Thomas. “The Role of Mitochondrial ATP-Binding Cassette Transporter ABCB6 in Metabolism and Energy Balance.” 2019. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/30121.

MLA Handbook (7^th Edition):

Tessman, Robert Thomas. “The Role of Mitochondrial ATP-Binding Cassette Transporter ABCB6 in Metabolism and Energy Balance.” 2019. Web. 19 Jan 2021.

Vancouver:

Tessman RT. The Role of Mitochondrial ATP-Binding Cassette Transporter ABCB6 in Metabolism and Energy Balance. [Internet] [Doctoral dissertation]. University of Kansas; 2019. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/30121.

Council of Science Editors:

Tessman RT. The Role of Mitochondrial ATP-Binding Cassette Transporter ABCB6 in Metabolism and Energy Balance. [Doctoral Dissertation]. University of Kansas; 2019. Available from: http://hdl.handle.net/1808/30121

University of Kansas

8. Zhang, Yuchen. IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2017, University of Kansas

URL: http://hdl.handle.net/1808/27333

► Many transporters are expressed at the basolateral membrane of human hepatocytes, including Organic Anion Transporting Polypeptide 1B1 (OATP1B1), OATP1B3, Organic Cation Transporter 1 (OCT1), Na+/Taurocholate… (more)

▼ Many transporters are expressed at the basolateral membrane of human hepatocytes, including Organic Anion Transporting Polypeptide 1B1 (OATP1B1), OATP1B3, Organic Cation Transporter 1 (OCT1), Na+/Taurocholate Cotransporting Polypeptide (NTCP) and more. These transporters are part of the absorption system of the liver, which is responsible for the uptake of chemicals from the portal vein into hepatocytes for further metabolism and elimination. Extensive studies have characterized the function of these transporters, and results suggest that liver uptake transporters, like OATP1B3 and OATP1B1, or OATP1B3 and NTCP, have many overlapping substrates. Because these transporters seem to play an essential role in the protection of the body from xenobiotics, it is important to better understand their function and how they interact with each other. In this dissertation, I focused on one of these transporter, OATP1B3, as a model transporter to improve the understanding of liver uptake transporters. OATP1B3 is responsible for the uptake of many endogenous compounds like bile acids and hormones as well as xenobiotics, including numerous drugs. Recent studies demonstrated that some of the liver uptake transporters like OATP1B1, OCT1 and NTCP can form homo-oligomers. In the first specific aim, I evaluated the hypothesis that OATP1B3 also can form homo-oligomers. To address this aim, co-immunoprecipitation and proximity ligation assays of differently tagged OATP1B3 were performed in transiently transfected HEK293 cells. The results demonstrated that OATP1B3 indeed can form homo-oligomers. In addition, uptake assays with wild-type and non-functional OATP1B3 suggested that the OATP1B3 unit in the homo-oligomers works as individual functional unit. Besides that, by using proximity ligation assays, the interaction between OATP1B3 and OATP1B1, and between OATP1B3 and NTCP was demonstrated in HEK293 cells. Interactions between OATP1B3 and NTCP were also confirmed in frozen liver sections. In the second specific aim, I evaluated the hypothesis that OATP1B3 can form hetero-oligomers with other transporters and that these interactions can influence their expression and function. I was able to extend the findings of hetero-oligomerization to include OCT1 using both immunoprecipitation and proximity ligation assays. Uptake assays and surface biotinylation experiments were performed with HEK293 cells co-expressing OATP1B3 and OCT1, OATP1B3 and OATP1B1, or OATP1B3 and NTCP. The results demonstrated that these interactions between OATP1B3 and the other transporters lead to changes in both, function and expression of OATP1B3 in a transporter-dependent manner. In the third specific aim, I evaluated the hypothesis that photoaffinity labeling can be used to study the binding sites and translocation pathways of OATP1B3. The known OATP1B3 substrate 8-fluorescein-cAMP (8-FcA) was used to perform photoaffinity labeling experiments with CHO Flp-In cells stably expressing His-tagged OATP1B3. The results suggested that 8-FcA can label proteins but background… Advisors/Committee Members: Hagenbuch, Bruno A (advisor), Blanco, V. Gustavo (cmtemember), Kasturi, Partha (cmtemember), Lampe, Jed N (cmtemember), Reed, Gregory A (cmtemember).

Subjects/Keywords: Pharmacology

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

APA (6^th Edition):

Zhang, Y. (2017). IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/27333

Chicago Manual of Style (16^th Edition):

Zhang, Yuchen. “IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3.” 2017. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/27333.

MLA Handbook (7^th Edition):

Zhang, Yuchen. “IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3.” 2017. Web. 19 Jan 2021.

Vancouver:

Zhang Y. IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3. [Internet] [Doctoral dissertation]. University of Kansas; 2017. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/27333.

Council of Science Editors:

Zhang Y. IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3. [Doctoral Dissertation]. University of Kansas; 2017. Available from: http://hdl.handle.net/1808/27333

University of Kansas

9. Bastola, Prabhakar. Targeting vulnerabilities through inhibiting the valosin-containing protein (VCP/p97) in ovarian cancer.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2018, University of Kansas

URL: http://hdl.handle.net/1808/27334

► Ovarian cancer is the fifth leading cause of cancer-related death among women and the deadliest of all gynecological cancers. Treatment failure is a major contributing… (more)

▼ Ovarian cancer is the fifth leading cause of cancer-related death among women and the deadliest of all gynecological cancers. Treatment failure is a major contributing factor in ovarian cancer-related mortality. Advances in the development of new agents that target critical pathways in cancer may provide better options to overcome treatment failure. One of the molecular mechanisms that can be targeted for ovarian cancer therapy is the protein quality control. Components of the protein quality control, such as heat shock proteins, the ubiquitin-proteasome system, the unfolded protein response and autophagy, regulate protein homeostasis. Protein quality control also provides phenotypic stability by buffering cryptic genetic variations that could potentially reduce the fitness of cancer cells. This concept was best illustrated by studies that genetically or pharmacologically inhibited heat-shock protein 90, and reported variations in the phenotype following the disruption of heat shock protein 90. This dissertation investigates the therapeutic efficacy of targeting valosin-containing protein (VCP), an important component of the protein quality control, in ovarian cancer. VCP or p97, a member of the ATPase Associated with diverse cellular Activities-ATPase (AAA-ATPase) protein family, has been associated with various cellular functions including endoplasmic reticulum associated degradation, the ubiquitin proteasome system, golgi membrane reassembly, autophagy, DNA repair and cell division making it an important regulator of the protein quality control. Recent studies identified VCP and the ubiquitin proteasome system as synthetic lethal targets in ovarian cancer. This dissertation describes the preclinical activity of VCP inhibitors in ovarian cancer. Results presented in this dissertation show that quinazoline-based VCP inhibitors initiate Gap 1 (G1) cell cycle arrest, attenuate cap-dependent protein translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis. Mechanistic studies point to the unresolved unfolded protein response as a mechanism by which VCP inhibitors contribute to cytotoxicity. These results support an emerging concept that the unfolded protein response pathway may be targeted in ovarian cancer as a source of vulnerability. Since prolonged induction of the unfolded protein response results in CCAAT/enhancer binding protein homologous protein (CHOP) mediated cell death, we tested the hypothesis that VCP inhibitors act synergistically with compounds that enhance CHOP expression. Here, we show that VCP inhibitors act synergistically with salubrinal, an inhibitor of growth arrest and DNA-damage-inducible 34 (GADD34), by enhancing CHOP expression in ovarian cancer cell lines. Our results provide a proof-of-concept that VCP inhibitors can be used as a single agent and can be synergized with compounds that enhance CHOP expression to induce cell death. While the synergistic effects observed between VCP inhibitors and GADD34 inhibitor provides an in vitro proof-of-concept,… Advisors/Committee Members: Ding, Wen-Xing (advisor), Chien, Jeremy (advisor), Hagenbuch, Bruno (cmtemember), Li, Tiangang (cmtemember), Fontes, Joseph D (cmtemember).

Subjects/Keywords: Pharmacology; endoplasmic reticulum stress; ovarian cancer; protein quality control; unfolded protein response; Valosin-containing protein; VCP/p97 inhibitors

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

APA (6^th Edition):

Bastola, P. (2018). Targeting vulnerabilities through inhibiting the valosin-containing protein (VCP/p97) in ovarian cancer. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/27334

Chicago Manual of Style (16^th Edition):

Bastola, Prabhakar. “Targeting vulnerabilities through inhibiting the valosin-containing protein (VCP/p97) in ovarian cancer.” 2018. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/27334.

MLA Handbook (7^th Edition):

Bastola, Prabhakar. “Targeting vulnerabilities through inhibiting the valosin-containing protein (VCP/p97) in ovarian cancer.” 2018. Web. 19 Jan 2021.

Vancouver:

Bastola P. Targeting vulnerabilities through inhibiting the valosin-containing protein (VCP/p97) in ovarian cancer. [Internet] [Doctoral dissertation]. University of Kansas; 2018. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/27334.

Council of Science Editors:

Bastola P. Targeting vulnerabilities through inhibiting the valosin-containing protein (VCP/p97) in ovarian cancer. [Doctoral Dissertation]. University of Kansas; 2018. Available from: http://hdl.handle.net/1808/27334

University of Kansas

10. Ogilvie, Brian Wayne. AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2015, University of Kansas

URL: http://hdl.handle.net/1808/19459

► Clopidogrel is a thienopyridine antiplatelet prodrug that was approved by the US FDA in 1997 and quickly supplanted ticlopidine as the primary drug therapy for… (more)

▼ Clopidogrel is a thienopyridine antiplatelet prodrug that was approved by the US FDA in 1997 and quickly supplanted ticlopidine as the primary drug therapy for reducing atherothrombotic events. It is converted to its pharmacologically active metabolite H4, which irreversibly inactivates the P2Y12 receptor on platelets, through two sequential reactions that are catalyzed mainly by CYP2C19. Common clinical practice involved the coadministration of a proton pump inhibitor (PPI, including omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) with clopidogrel to decrease the risk of upper gastrointestinal bleeding. This practice was formalized for high risk patients by the American Heart Association (and others) in 2008. By 2009, numerous publications described an unexpected decrease in clopidogrel efficacy when coadministered with PPIs, prompting both the US Food & Drug Administration (FDA) and European Medicines Agency (EMA) to issue recommendations discouraging the concomitant use of PPIs and clopidogrel. Proton pump inhibitors are also metabolized by CYP2C19. It seemed reasonable to conclude that, despite their relatively short plasma half-lives, PPIs might competitively inhibit CYP2C19, thereby reducing the efficacy of clopidogrel. In 2010, as numerous publications emerged, both regulatory agencies restricted subsequent warnings to only omeprazole and esomeprazole. The interaction between clopidogrel and PPIs, and the potential mechanisms responsible for it, continues to be a subject of much debate in 2015. This dissertation describes research that contributes to the progress made in understanding the basis for the interaction between clopidogrel and PPIs since the time of the initial regulatory statements, and in particular, why only omeprazole and esomeprazole are implicated in this drug interaction. The initial studies in this dissertation identified omeprazole (a racemic mixture of R- and S-enantiomers) and esomeprazole (the S-enantiomer) as not only competitive inhibitors, but more importantly, metabolism-dependent inhibitors (MDIs) of CYP2C19 in human liver microsomes (HLM), human hepatocytes and recombinant CYP2C19. In contrast, lansoprazole and pantoprazole did not cause metabolism-dependent inhibition (MDI) of CYP2C19. In addition to its clinical relevance, these observations are important because they underscore the importance of using a low concentration of enzyme and a short incubation time with the CYP marker substrate in order to detect MDI of CYP enzymes in vitro. In many previous studies of CYP2C19 inhibition by omeprazole or esomeprazole, the concentration of HLM was too high and/or the substrate incubation time was too long to detect MDI. The kinetic parameters for CYP2C19 inactivation by omeprazole, namely kinact and KI, were determined and used in a physiologically based pharmacokinetic (PBPK) model to predict the degree of CYP2C19 inactivation under clinical conditions. Omeprazole and esomeprazole were subsequently shown to be irreversible MDIs of CYP2C19, which explained why the… Advisors/Committee Members: Reed, Gregory A (advisor), Parkinson, Andrew (advisor), Hagenbuch, Bruno (cmtemember), Weir, Scott (cmtemember), Hanzlik, Robert P (cmtemember).

Subjects/Keywords: Toxicology; Clopidogrel; Cytochrome P450; Drug-drug interactions; Esomeprazole; Omeprazole

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

APA (6^th Edition):

Ogilvie, B. W. (2015). AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/19459

Chicago Manual of Style (16^th Edition):

Ogilvie, Brian Wayne. “AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL.” 2015. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/19459.

MLA Handbook (7^th Edition):

Ogilvie, Brian Wayne. “AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL.” 2015. Web. 19 Jan 2021.

Vancouver:

Ogilvie BW. AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL. [Internet] [Doctoral dissertation]. University of Kansas; 2015. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/19459.

Council of Science Editors:

Ogilvie BW. AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL. [Doctoral Dissertation]. University of Kansas; 2015. Available from: http://hdl.handle.net/1808/19459

11. Roth, Megan Elizabeth. Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3).

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

URL: http://hdl.handle.net/1808/9715

► Organic anion transporting polypeptides (OATPs) are multispecific transporters that mediate the uptake of numerous drugs and xenobiotics into cells. Alterations in the function of the… (more)

▼ Organic anion transporting polypeptides (OATPs) are multispecific transporters that mediate the uptake of numerous drugs and xenobiotics into cells. Alterations in the function of the liver–specific OATP1B1 and OATP1B3 have been shown to affect the disposition of drugs throughout the body. It has been proposed that new drug candidates should be screened for possible OATP inhibition using a prototypical substrate such as estradiol–17β–glucuronide. However, there is evidence that OATPs may have multiple binding sites, and therefore screening with a single compound may be ineffective. Therefore, I tested the hypothesis that OATP1B3 has multiple overlapping but distinct binding sites, which are affected in substrate–dependent ways. This hypothesis was tested via two specific aims: 1) to identify and characterize substrate–dependent effects of plant compounds on OATP1B3–mediated transport, and 2) to identify regions of OATP1B3 involved in the binding and/or translocation of individual model substrates. In the first specific aim, interacting compounds were identified by screening a library of plant compounds for inhibition or stimulation of OATP–mediated uptake of two model substrates. Completion of this specific aim identified two structurally similar compounds that produce substrate–dependent effects on OATP1B3–mediated transport. These compounds stimulate transport of estrone–3–sulfate by increasing substrate affinity. However, the compounds either inhibit or have no effect on the uptake of estradiol–17β–glucuronide. These results demonstrate that estrone–3–sulfate and estradiol–17β–glucuronide have distinct binding sites on OATP1B3. In specific aim two, thirty–three amino acids in the first transmembrane domain and extracellular loop of OATP1B3 were individually mutated to cysteines, and I determined the effect of these mutations on the transport of estradiol-17β-glucuronide and estrone–3–sulfate. Five of the cysteine–substituted OATP1B3 mutants produced different effects on transporter function depending upon the substrate tested. These results suggest that this region of OATP1B3 is involved in the recognition and translocation of individual model substrates. This dissertation demonstrates that OATP1B3 has distinct binding sites for estradiol–17β–glucuronide and estrone–3–sulfate. Furthermore, it shows that transport of these two model substrates is affected in different ways by the same compounds. This knowledge can be used to improve screening of drug candidates to prevent adverse drug–drug interactions prior to the occurrence of adverse events. Advisors/Committee Members: Hagenbuch, Bruno (advisor), Krishnamurthy, Partha (cmtemember), Reed, Gregory A. (cmtemember), Timmermann, Barbara N (cmtemember), Zhu, Bao-Ting (cmtemember).

Subjects/Keywords: Pharmacology; Physiology; Drug-drug interactions; Oatp; Structure-function; Transporters

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

APA (6^th Edition):

Roth, M. E. (2011). Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3). (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/9715

Chicago Manual of Style (16^th Edition):

Roth, Megan Elizabeth. “Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3).” 2011. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/9715.

MLA Handbook (7^th Edition):

Roth, Megan Elizabeth. “Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3).” 2011. Web. 19 Jan 2021.

Vancouver:

Roth ME. Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3). [Internet] [Doctoral dissertation]. University of Kansas; 2011. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/9715.

Council of Science Editors:

Roth ME. Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3). [Doctoral Dissertation]. University of Kansas; 2011. Available from: http://hdl.handle.net/1808/9715

University of Kansas

12. Flynn, Colleen A. FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS.

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

URL: http://hdl.handle.net/1808/9723

► Transporters play a major role in the absorption and disposition of fexofenadine, suggesting this drug could be used as a probe of transporter activity. When… (more)

▼ Transporters play a major role in the absorption and disposition of fexofenadine, suggesting this drug could be used as a probe of transporter activity. When fexofenadine was administered in combination with four drugs (buspirone, caffeine, dextromethorphan and losartan) used to probe cytochrome P450 (CYP) activities, a significant decrease in fexofenadine AUC was observed without a change in elimination. Based on this observation, I hypothesized a fexofenadine-probe drug interaction was occurring during oral absorption, and that this interaction was occurring at an enterocyte-expressed OATP. This interaction was reproduced and studied using in vitro model systems. In Specific Aim 1, a specific LC-MS/MS method was developed and validated for the quantification of fexofenadine and the other four probe drugs for use in the remaining specific aims. In Specific Aim 2, the interaction between fexofenadine and four enterocyte- and hepatocyte-expressed OATPs was characterized, and OATP1A2 was identified as the most effective transporter of fexofenadine, with a Km of 35 μM. Because fexofenadine was efficiently transported by OATP1A2, the four CYP probe drugs were tested as inhibitors of OATP1A2-mediated fexofenadine transport in Specific Aim 3. Buspirone, losartan, and dextromethorphan each inhibited OATP1A2-mediated fexofenadine transport in a concentration dependent manner. This inhibition could explain the decrease in fexofenadine oral bioavailability seen in the clinical study we had previously conducted. The replication of the fexofenadine-probe drug interaction in this model system supports the conclusion that OATP1A2 is the major uptake transporter for fexofenadine absorption in the enterocyte, and suggests that fexofenadine may be an effective probe drug for this transporter. In Specific Aim 4, I further characterized the fexofenadine-probe drug interactions using the three known OATP1A2 polymorphisms: Ile13Thr, Arg168Cys, and Glu172Asp. While the mutants functioned as expected with regard to fexofenadine transport, the presence of the mutation did not alter the observed drug-drug interactions seen previously with OATP1A2 and the CYP probes. Taking these data into account, it appears the fexofenadine-drug interaction seen previously is not affected by single nucleotide polymorphisms. This work demonstrates that OATP1A2 is capable of transporting fexofenadine and that several CYP probe drugs inhibit its transport by OATP1A2. This latter observation limits the utility of fexofenadine to be used as a single probe, rather than as part of a probe drug cocktail. Advisors/Committee Members: Reed, Gregory A (advisor), Durham, Dianne (cmtemember), Hagenbuch, Bruno (cmtemember), Lampe, Jed N. (cmtemember), Pazdernik, Thomas L. (cmtemember).

Subjects/Keywords: Toxicology; Drug-drug interactions; Fexofenadine; Oatp; Probe cocktail; Single nucleotide polymorphism

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

APA (6^th Edition):

Flynn, C. A. (2011). FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/9723

Chicago Manual of Style (16^th Edition):

Flynn, Colleen A. “FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS.” 2011. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/9723.

MLA Handbook (7^th Edition):

Flynn, Colleen A. “FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS.” 2011. Web. 19 Jan 2021.

Vancouver:

Flynn CA. FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS. [Internet] [Doctoral dissertation]. University of Kansas; 2011. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/9723.

Council of Science Editors:

Flynn CA. FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS. [Doctoral Dissertation]. University of Kansas; 2011. Available from: http://hdl.handle.net/1808/9723

University of Kansas

13. Boxberger, Kelli Harmon. IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2018, University of Kansas

URL: http://hdl.handle.net/1808/27078

► The human organic cation transporter 1 (hOCT1) is a polyspecific transporter, primarily expressed in the liver, which is known to interact with a large number… (more)

▼ The human organic cation transporter 1 (hOCT1) is a polyspecific transporter, primarily expressed in the liver, which is known to interact with a large number of structurally dissimilar compounds. Several clinically-relevant drugs, as well as some endogenous compounds and other xenobiotics have been shown to be transported by or inhibit hOCT1. Due to its hepatic expression and general ADME function, hOCT1 has been implicated in adverse drug events (ADEs), including drug-drug interactions. As such, multiple regulatory agencies recommend including hOCT1, in pre-clinical transporter interaction studies. Limited structural information is available for hOCT1, and recently, endogenous functions and substrate-dependent effects have been identified for close relatives of hOCT1. Taken together, these suggest a need for further scrutiny of hOCT1 structure-activity relationships for development of critical drug-transporter interaction studies. The hypothesis was developed that both endogenous and xenobiotic compounds modulate the functional activity of hOCT1 in a substrate-dependent manner through interaction with specific, but perhaps distinct ligand-binding domains within the transporter. The hypothesis was tested via the following specific aims: 1) investigate the effect of xenobiotics on endogenous substrate transport by hOCT1, 2) identify and characterize substrate-dependent interactions with hOCT1, and 3) examine the role of the extracellular loop domain of hOCT1 in substrate affinity and translocation. In the first specific aim, dopamine and serotonin were identified as substrates for hOCT1. Serotonin proved to be a moderate-affinity substrate, while hOCT1 was able to transport it at high capacity. Several clinically-relevant drugs inhibited hOCT1-mediated serotonin transport, and these results were capitulated in primary human hepatocytes. Combined data from this inhibition screen and those previously published by other groups suggested the possibility of substrate-dependent effects. In specific aim two, substrate-dependent effects were screened for in a relatively new assay method, competitive counterflow (CCF). The CCF assay allowed for identification of novel substrates for hOCT1, including negatively-charged bromosulfophthalein (BSP). CCF results also identified numerous substrate-dependent effects which were explored further using computational (homology) modeling and ligand docking. Docking experiments identified three distinct binding sites within the hOCT1 homology model which explain several of the overserved substrate-dependent interactions, and supports previous claims that hOCT1 has a large substrate binding region versus a singular binding site and may be the reason for hOCT1’s polyspecificity. In the final specific aim, an attempt was made to generate human and rat OCT1 chimeric proteins. The goal of this study was to examine the role of the extracellular loop (ECL) domain in the observed differences in substrate affinity between species. Issues during the cloning process prevented the completion of this… Advisors/Committee Members: Hagenbuch, Bruno (advisor), Lampe, Jed N (cmtemember), Pritchard, Michele T (cmtemember), Reed, Gregory A (cmtemember), Blanco, V. Gustavo (cmtemember).

Subjects/Keywords: Pharmacology; computational modeling; drug disposition; drug-drug interactions; organic cation transporter; substrate-dependent interactions; transporters

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

APA (6^th Edition):

Boxberger, K. H. (2018). IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/27078

Chicago Manual of Style (16^th Edition):

Boxberger, Kelli Harmon. “IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1.” 2018. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/27078.

MLA Handbook (7^th Edition):

Boxberger, Kelli Harmon. “IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1.” 2018. Web. 19 Jan 2021.

Vancouver:

Boxberger KH. IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1. [Internet] [Doctoral dissertation]. University of Kansas; 2018. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/27078.

Council of Science Editors:

Boxberger KH. IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1. [Doctoral Dissertation]. University of Kansas; 2018. Available from: http://hdl.handle.net/1808/27078

University of Kansas

14. Curry, Joshua Nicholas. The role of claudin-2 in the proximal tubule and kidney stone disease.

Degree: PhD, Molecular & Integrative Physiology, 2018, University of Kansas

URL: http://hdl.handle.net/1808/30132

► The concentration of circulating blood calcium is vital to the function of many cellular processes. As such, it is maintained within a narrow range through… (more)

▼ The concentration of circulating blood calcium is vital to the function of many cellular processes. As such, it is maintained within a narrow range through the actions of gastrointestinal, bone, kidney, and endocrine tissues. In the kidney, the first portion of the nephron, called the proximal tubule (PT), performs the majority of solute reabsorption including about two-thirds of calcium. In vivo and ex vivo studies of PTs have shown that the major component of calcium reabsorption is passive and tightly linked to sodium reabsorption. This passive transport has long been suspected to be paracellular. The precise mechanisms and molecular facilitators of calcium reabsorption in the PT, however, remain unknown. Claudins are a group of transmembrane tight junction (TJ) proteins that are vital to the regulation of paracellular transport. In the PT, claudin-2 is a highly expressed isoform. Claudin-2 increases the calcium permeability of renal epithelial cells upon overexpression. In addition, it was previously shown that mice with deletion of claudin-2 have increased urinary calcium excretion. I hypothesized that PT calcium reabsorption is facilitated by claudin-2. My overall hypothesis was tested in several ways. First, I examined the patterns of claudin expression in the proximal nephron and found that claudins-2 and -10a are expressed throughout the PT, in both convoluted and straight segments. In contrast, claudin-3 is expressed only within the proximal straight tubule (PST). Furthermore, claudin-2 and claudin-3 expression are found in separate and distinct subpopulations of thin descending limbs. Next, I used co-immunoprecipitation experiments to show that claudin-2 physically interacts with claudin-3. Then I generated renal epithelial cell lines with inducible expression of PT claudins, claudin-2 and either claudin-3 or claudin-10a. I found no effect of claudin-3 overexpression on conductance or sodium permeability (PNa), with or without claudin-2 expression. However, overexpression of both claudins-2 and -10a led to a highly conductive cell monolayer with loss of charge selectivity. The results of calcium permeability assays show that calcium transport was reduced with co-expression of claudins-2 and -10a but unchanged with co-expression of claudins-2 and -3. In order to test the potential contribution of claudin hetero-oligomerization on these permeability properties, I measured permeability of claudin-2/claudin-10a cells with titrated expression of each protein and with blockage of the claudin-2 pore. My results suggest that, rather than forming a hybrid channel with novel characteristics, claudin-2 and claudin-10a form pores in parallel. Next, I tested the hypothesis that deletion of the claudin-2 gene Cldn2 in mice causes nephrocalcinosis similar to human kidney stone disease using micro-computed tomography (micro-CT) and histological analyses. My findings indicate that this papillary pattern of nephrocalcinosis shares striking similarities to human kidney stone disease. I also examined the mechanism of… Advisors/Committee Members: Yu, Alan S.L. (advisor), Blanco, V. Gustavo (advisor), Hagenbuch, Bruno (cmtemember), Fields, Timothy (cmtemember), Rowe, Peter (cmtemember), Wallace, Darren (cmtemember), Stubbs, Jason (cmtemember).

Subjects/Keywords: Physiology; Genetics; Medicine; calcium; claudins; ion transport; kidney stones; nephrocalcinosis; tight junctions

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APA (6^th Edition):

Curry, J. N. (2018). The role of claudin-2 in the proximal tubule and kidney stone disease. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/30132

Chicago Manual of Style (16^th Edition):

Curry, Joshua Nicholas. “The role of claudin-2 in the proximal tubule and kidney stone disease.” 2018. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/30132.

MLA Handbook (7^th Edition):

Curry, Joshua Nicholas. “The role of claudin-2 in the proximal tubule and kidney stone disease.” 2018. Web. 19 Jan 2021.

Vancouver:

Curry JN. The role of claudin-2 in the proximal tubule and kidney stone disease. [Internet] [Doctoral dissertation]. University of Kansas; 2018. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/30132.

Council of Science Editors:

Curry JN. The role of claudin-2 in the proximal tubule and kidney stone disease. [Doctoral Dissertation]. University of Kansas; 2018. Available from: http://hdl.handle.net/1808/30132

15. Holt, Briana. Early growth response (Egr)-1: A novel anti-fibrotic mediator in liver.

Degree: MS, Pharmacology, Toxicology & Therapeutics, 2014, University of Kansas

URL: http://hdl.handle.net/1808/18422

► Chronic alcohol consumption can lead to an aberrant wound healing response of the liver, or hepatic fibrosis. Egr-1 is an essential regulator of many genes… (more)

▼ Chronic alcohol consumption can lead to an aberrant wound healing response of the liver, or hepatic fibrosis. Egr-1 is an essential regulator of many genes involved in the orchestration of tissue injury and repair, yet the implications of Egr-1 in different models of liver disease remain unclear. Previously, we demonstrated that carbon tetrachloride (CCl4)-induced hepatic fibrosis is enhanced in Egr-1 deficient mice. In this study, we investigated the role of Egr-1 in the attenuation of early markers of hepatic fibrosis using a model of ethanol-accelerated, CCl4-induced liver injury in wild-type and Egr-1 deficient mice. Whereas Egr-1 mRNA was induced 100-fold in livers from wild-type mice 48h after CCl4 exposure, ethanol feeding reduced Egr-1 expression by 50 percent. Seventy-two hours after CCl4 exposure, hepatic mRNA accumulation of type I collagen and αSMA, markers of fibrogenesis expressed by activated hepatic stellate cells (HSC), were increased 22-fold and 20-fold, respectively, in both wild-type and Egr-1 -/- mice; levels of these transcripts were greater in ethanol-fed, Egr-1 -/- mice. Consistently, plate-induced activation of HSC from Egr-1 deficient mice was increased relative to HSC from wild-type mice. Previous use of an oxidant stress, antioxidant defense pathway array identified genes differentially expressed in ethanol-fed, Egr-1 -/- mice compared to ethanol-fed, wild-type mice after CCl4 exposure. We examined one of these genes, NAD(P)H dehydrogenase, quinone 1 (Nqo1), and found that Nqo1 mRNA and protein was reduced in Egr-1 -/- mice relative to wild-type mice 72h after CCl4 exposure, and ethanol feeding exacerbated this reduction. Consistently, chromatin from livers of wild-type, CCl4-treated mice confirmed association between Egr-1 and the Nqo1 promoter upon immunoprecipitation with an Egr-1 antibody. Although Egr-1 deficient mice did not demonstrate inhibited oxidation of NADH after CCl4 via loss of Nqo1, β-lapachone-mediated stimulation of Nqo1 activity suppressed CCl4-induced liver injury and fibrogenic changes. Collectively, these data support the hypothesis that Egr-1 attenuates early markers of hepatic fibrosis, and here we propose that Nqo1, a previously unrecognized target of Egr-1, is a contributing factor Advisors/Committee Members: Pritchard, Michele T (advisor), Hagenbuch, Bruno (cmtemember), Woods, John (cmtemember).

Subjects/Keywords: Toxicology

…Use Committee at the University of Kansas Medical Center. Mice deficient in Egr-1 were bred…

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APA (6^th Edition):

Holt, B. (2014). Early growth response (Egr)-1: A novel anti-fibrotic mediator in liver. (Masters Thesis). University of Kansas. Retrieved from http://hdl.handle.net/1808/18422

Chicago Manual of Style (16^th Edition):

Holt, Briana. “Early growth response (Egr)-1: A novel anti-fibrotic mediator in liver.” 2014. Masters Thesis, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/18422.

MLA Handbook (7^th Edition):

Holt, Briana. “Early growth response (Egr)-1: A novel anti-fibrotic mediator in liver.” 2014. Web. 19 Jan 2021.

Vancouver:

Holt B. Early growth response (Egr)-1: A novel anti-fibrotic mediator in liver. [Internet] [Masters thesis]. University of Kansas; 2014. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/18422.

Council of Science Editors:

Holt B. Early growth response (Egr)-1: A novel anti-fibrotic mediator in liver. [Masters Thesis]. University of Kansas; 2014. Available from: http://hdl.handle.net/1808/18422

16. Pei, Lei. PARACELLULAR EPITHELIAL TRANSPORT MAXIMIZES ENERGY EFFICIENCY IN THE KIDNEY.

Degree: PhD, Molecular & Integrative Physiology, 2016, University of Kansas

URL: http://hdl.handle.net/1808/22506

► Claudins are tight junction transmembrane proteins that act as paracellular ion channels. The proximal renal tubule reabsorbs 70% of glomerulus-filtered Na+. Of this Na+, up… (more)

▼ Claudins are tight junction transmembrane proteins that act as paracellular ion channels. The proximal renal tubule reabsorbs 70% of glomerulus-filtered Na+. Of this Na+, up to 1/3 is reabsorbed passively via the paracellular pathway. Claudin-2 has been shown to mediate paracellular sodium reabsorption in the proximal tubule of the kidney. Claudin-2 null mice are reported to have markedly decreased proximal tubule Na+, Cl- and fluid reabsorption, but they have no apparent disturbance in overall Na+ balance. We investigated whether we can uncover the salt-wasting phenotype of claudin-2 knockout mice by challenging them with Na+ depletion. Even during profound dietary sodium depletion, claudin-2 null mice demonstrated the ability to conserve sodium to the same extent as wild-type mice. We investigated how the Na+ wasted from the proximal tubule was compensated in other segments of the renal tubule. We performed immunoblot on transcellular Na+ transporters Na-H antiporter 3, Na-K-2Cl cotransporter, NaCl cotransporter and epithelial Na+ channel. We found no upregulation of the protein abundance of any of these transcellular transporters. To test whether there was functional upregulation of transcellular Na+ transport distally, diuretic challenge tests were performed. The natriuresis 4 hours after intraperitoneal furosemide (but not after hydrochlorothiazide or benzamil) was 40% higher in claudin-2 null mice than in WT mice, indicating that the site of compensation was the thick ascending limb. We concluded that claudin-2 null mice are able to conserve sodium to the same extent as wild-type mice, even under extreme conditions, due to upregulation of transcellular Na-K-2Cl transport activity in the thick ascending limb of Henle. We therefore hypothesized that the shifting of sodium transport to transcellular pathways would lead to increased whole kidney oxygen consumption. Indeed we found that the kidneys of claudin-2 null mice have markedly increased oxygen consumption despite normal sodium reabsorption, and consequently have medullary hypoxia. Furthermore, when subjected to bilateral renal ischemia-reperfusion injury, kidneys of claudin-2 null mice exhibited more severe tubular injury. In summary, our findings suggest a more important reason for the existence of the paracellular transport pathway, namely that it evolved to enhance the efficiency of energy and oxygen utilization by the renal tubule epithelium. Our research demonstrates that claudin-2 is a key paracellular pathway for passive Na+ absorption in the proximal tubule that reduces the overall energy expenditure by the kidneys. This dissertation sheds light on a fundamental metabolic process and thereby provides insight on the process that may have broader significance for epithelial tissues. Advisors/Committee Members: Yu, Alan S.L. (advisor), Hagenbuch, Bruno (cmtemember), Blanco, Gustavo (cmtemember), Rao, Reena (cmtemember), Wallace, Darren (cmtemember).

Subjects/Keywords: Physiology; acute kidney injury; claudin-2; Hypoxia; oxygen utilization efficiency

…Care and Use Committee at the University of Kansas Medical Center. Data analysis Data are…

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APA (6^th Edition):

Pei, L. (2016). PARACELLULAR EPITHELIAL TRANSPORT MAXIMIZES ENERGY EFFICIENCY IN THE KIDNEY. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/22506

Chicago Manual of Style (16^th Edition):

Pei, Lei. “PARACELLULAR EPITHELIAL TRANSPORT MAXIMIZES ENERGY EFFICIENCY IN THE KIDNEY.” 2016. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/22506.

MLA Handbook (7^th Edition):

Pei, Lei. “PARACELLULAR EPITHELIAL TRANSPORT MAXIMIZES ENERGY EFFICIENCY IN THE KIDNEY.” 2016. Web. 19 Jan 2021.

Vancouver:

Pei L. PARACELLULAR EPITHELIAL TRANSPORT MAXIMIZES ENERGY EFFICIENCY IN THE KIDNEY. [Internet] [Doctoral dissertation]. University of Kansas; 2016. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/22506.

Council of Science Editors:

Pei L. PARACELLULAR EPITHELIAL TRANSPORT MAXIMIZES ENERGY EFFICIENCY IN THE KIDNEY. [Doctoral Dissertation]. University of Kansas; 2016. Available from: http://hdl.handle.net/1808/22506

17. Walesky, Chad Michael. Role of Hepatocyte Nuclear Factor 4 alpha in Hepatocyte Proliferation.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2014, University of Kansas

URL: http://hdl.handle.net/1808/14505

► Hepatocyte Nuclear Factor 4 alpha (HNF4α) is the master regulator of hepatocyte differentiation. It is involved in the up-regulation of genes involved in many classic… (more)

▼ Hepatocyte Nuclear Factor 4 alpha (HNF4α) is the master regulator of hepatocyte differentiation. It is involved in the up-regulation of genes involved in many classic hepatic functions including: bile acid metabolism, xenobiotic metabolism, glucose homeostasis, lipid metabolism, coagulation factor synthesis, etc. However, the role of HNF4α in regulation of hepatocyte proliferation was not known. The primary goal of this dissertation was to investigate the role of HNF4α in the regulation of hepatocyte proliferation. In these studies we utilized two novel inducible, hepatocyte specific, HNF4α knockdown mouse models. Past models of HNF4α dificiency result in deletion within the first few weeks of birth and lead to lethality within 6-8 weeks. This makes it difficult to address a role for HNF4α in hepatocyte proliferation because the liver is still growing and differentiating within this time frame. Hepatocyte-specific deletion of HNF4α in adult mice resulted in fat accumulation (steatosis), glycogen depletion, and increased hepatocyte proliferation with a significant increase in liver/body weight ratio without complimentary liver regeneration due to hepatocyte cell death. Global gene expression analysis (microarray and RNA-Seq) revealed that a significant number of the 300+ down-regulated genes are involved in hepatic differentiation, many of which are known HNF4α targets. Interestingly, a significant number of the 500+ up-regulated genes are associated with cell proliferation and cancer. Further, a combined bioinformatics analysis of ChIP-sequencing and RNA-sequencing data indicated that a substantial number of up-regulated genes are putative HNF4α targets. We have used chromatin immunoprecipitation (ChIP) to confirm three of these targets: Ect2, Osgin1, and Hjurp. Ingenuity Pathway Analysis (IPA)-mediated functional analysis revealed the most significantly activated gene network after HNF4α deletion is regulated by c-Myc. To determine the role of HNF4α in pathogenesis of hepatocellular carcinoma (HCC), we performed the classic initiation-promotion experiment using diethylnitrosamine (DEN). Deletion of HNF4α resulted in extensive promotion of DEN-induced hepatic tumors, which were highly proliferative and less differentiated. Further, the HCC observed in HNF4α-deleted mice exhibited significant up-regulation of c-Myc and its target genes. We hypothesized that HNF4α inhibits hepatocyte proliferation by repression of target genes. One possible mechanism is that HNF4α influences the epigenetic state of a given gene to promote or inhibit gene expression. We studied various epigenetic modifications associated with gene activation and repression on a 9 kb segment of the promoter of Ect2, a validated HNF4α negative target gene also known to activate hepatocyte proliferation. ChIP analysis performed on chromatin isolated from control and HNF4α KO livers indicated that a deletion of HNF4α resulted in an epigenetic switch in histone modifications at the Ect2 promoter from an inhibited to an active state; primarily affecting… Advisors/Committee Members: Apte, Udayan (advisor), Jaeschke, Hartmut (cmtemember), Hagenbuch, Bruno (cmtemember), Pritchard, Michele (cmtemember), Weinman, Steven (cmtemember).

Subjects/Keywords: Toxicology; Cancer; Gene expression; Hepatocyte; Hepatocyte nuclear factor 4; Liver; Proliferation

…University of Kansas Medical Center under a standard 12-h light/dark cycle with access to chow and…

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APA (6^th Edition):

Walesky, C. M. (2014). Role of Hepatocyte Nuclear Factor 4 alpha in Hepatocyte Proliferation. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/14505

Chicago Manual of Style (16^th Edition):

Walesky, Chad Michael. “Role of Hepatocyte Nuclear Factor 4 alpha in Hepatocyte Proliferation.” 2014. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/14505.

MLA Handbook (7^th Edition):

Walesky, Chad Michael. “Role of Hepatocyte Nuclear Factor 4 alpha in Hepatocyte Proliferation.” 2014. Web. 19 Jan 2021.

Vancouver:

Walesky CM. Role of Hepatocyte Nuclear Factor 4 alpha in Hepatocyte Proliferation. [Internet] [Doctoral dissertation]. University of Kansas; 2014. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/14505.

Council of Science Editors:

Walesky CM. Role of Hepatocyte Nuclear Factor 4 alpha in Hepatocyte Proliferation. [Doctoral Dissertation]. University of Kansas; 2014. Available from: http://hdl.handle.net/1808/14505

18. Sullivan, Bradley P. Role of Coagulation in Xenobiotic-Induced Liver Injury.

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

URL: http://hdl.handle.net/1808/10291

► The liver is a common target for xenobiotic-induced toxicity. Of importance, synthesis of soluble coagulation factors by the liver plays an essential role in hemostasis.… (more)

▼ The liver is a common target for xenobiotic-induced toxicity. Of importance, synthesis of soluble coagulation factors by the liver plays an essential role in hemostasis. Blood coagulation cascade activation is evident in both human patients and in animal models of liver injury. Several studies have shown that coagulation is not merely a process reactive to toxicity, but rather a critical determinant of liver disease pathogenesis. Previous studies have utilized global anticoagulation as a strategy to investigate the role of coagulation in liver injury. Currently, our understanding of the mechanisms whereby individual coagulation proteases contribute to hepatotoxicity is inadequate. Blood coagulation is initiated by tissue factor (TF), a transmembrane cellular receptor for the coagulation factor VII/VIIa. The TF:VIIa complex initiates a serine protease cascade, which culminates in the generation of the serine protease thrombin. Thrombin cleaves circulating fibrinogen to initiate fibrin clot formation. Additionally, thrombin signals to multiple cell types through activation of protease activated receptors (PARs), which can promote inflammation and platelet aggregation. The procoagulant response is balanced by several anticoagulant proteins and fibrin clot degradation is catalyzed by plasmin, the main endogenous fibrin degradation enzyme. The aim of this dissertation was to determine the role of several blood coagulation cascade components in the responses elicited by two model hepatotoxicants; &alpha-naphthylisothiocyanate (ANIT) a toxicant that damages bile duct epithelial cells (BDECs), and acetaminophen (APAP), a common analgesic that causes centrilobular hepatocellular necrosis at high doses. We found that TF-dependent generation of thrombin contributed to the progression of chronic ANIT-induced hepatic inflammation and fibrosis by a mechanism requiring PAR-1. PAR-1 activation amplified TGF-&beta1-induced &alphaV&beta6 integrin expression by BDECs, and activation of TGF-&beta signaling in vivo. This suggests a novel feed-forward mechanism whereby coagulation can promote fibrogenesis. In contrast, PAR-1 was not required for the acute hepatotoxic effects of ANIT. Rather, ANIT-induced liver injury occurred by a mechanism involving activation of PAR-4 on platelets and fibrin(ogen). The results highlight a differential contribution of thrombin signaling in acute and chronic cholestatic liver injury. Previous studies identified the primary inhibitor of fibrinolysis, plasminogen activator inhibitor-1 (PAI-1), as a key hepatoprotective factor in APAP-induced liver injury. Indeed, hepatic fibrin deposition is a prominent feature of APAP-induced hepatocellular necrosis. To our surprise, fibrin(ogen) did not contribute to acute APAP-induced liver injury. Of importance, plasminogen deficiency reduced APAP hepatotoxicity. Taken together, the results suggest that plasmin(ogen) promotes APAP-induced liver injury in a fibrin independent manner. Overall, these studies revealed novel pathways whereby elements of the coagulation… Advisors/Committee Members: Hagenbuch, Bruno (advisor), Luyendyk, James P (advisor), Kasturi, Partha (cmtemember), Jaeschke, Hartmut (cmtemember), Wood, John (cmtemember).

Subjects/Keywords: Toxicology; Acetaminophen; Alpha-naphthylisothiocyanate; Blood coagulation; Fibrosis; Liver injury; Platelet

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APA (6^th Edition):

Sullivan, B. P. (2012). Role of Coagulation in Xenobiotic-Induced Liver Injury. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/10291

Chicago Manual of Style (16^th Edition):

Sullivan, Bradley P. “Role of Coagulation in Xenobiotic-Induced Liver Injury.” 2012. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/10291.

MLA Handbook (7^th Edition):

Sullivan, Bradley P. “Role of Coagulation in Xenobiotic-Induced Liver Injury.” 2012. Web. 19 Jan 2021.

Vancouver:

Sullivan BP. Role of Coagulation in Xenobiotic-Induced Liver Injury. [Internet] [Doctoral dissertation]. University of Kansas; 2012. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/10291.

Council of Science Editors:

Sullivan BP. Role of Coagulation in Xenobiotic-Induced Liver Injury. [Doctoral Dissertation]. University of Kansas; 2012. Available from: http://hdl.handle.net/1808/10291

19. Thomas, Ann M. THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER.

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

URL: http://hdl.handle.net/1808/8386

► Farnesoid X receptor (FXR) is a ligand activated transcription factor belonging to the nuclear receptor superfamily and bile acids are its endogenous ligands. FXR is… (more)

▼ Farnesoid X receptor (FXR) is a ligand activated transcription factor belonging to the nuclear receptor superfamily and bile acids are its endogenous ligands. FXR is a critical regulator of the enterohepatic circulation of bile acids, lipid homeostasis, glucose metabolism, and tumor suppression in liver and intestine. Consequently, FXR has become a very promising therapeutic target for the prevention and/or treatment of cholestasis, hyperlipidemic disorders, metabolic syndrome, and liver and colon cancer. Studies suggest epigenetic mechanisms are critical for proper transcriptional induction of nuclear receptors. Likewise, evidence shows epigenetic mechanisms are responsible for modulating the tissue/cell-specific FXR expression in human colon cancer. However, how epigenetic mechanisms are involved in FXR induced transcription or tissue-specific FXR expression remains elusive. Understanding these mechanisms is crucial for future development of pharmacological modulators of FXR as well as understanding the full physiological roles of FXR. This dissertation was designed to elucidate epigenetic mechanisms involved in tissue-specific FXR induced gene transcription, orphan nuclear receptors critical for regulating FXR function, and epigenetic mechanisms responsible for FXR silencing in colon cancer. In specific aim 1, a genome-wide FXR binding assay was done in mouse liver and intestine. Specific aim 2 focuses on the role of the orphan nuclear receptor hepatocyte nuclear factor 4fnalpha (HNF4&alpha) in regulating liver-specific functions of FXR. And finally, in specific aim 3, DNA methylation of FXR promoter was investigated as the mechanism responsible for FXR silencing in human colon cancer. In conclusion, genome-wide binding of FXR implicates novel epigenetic mechanisms and orphan nuclear receptors in regulating FXR function. Furthermore, this study indicates that HNF4&alpha is at least one orphan nuclear receptor capable of regulating FXR function in the liver. Findings from these first two aims succeeded in progressing drug development fields aimed at finding new FXR modulators for the treatment of multiple metabolic disorders by elucidating novel epigenetic mechanisms that may be investigated as therapeutic targets. Finally, FXR is at least partially down-regulated by DNA methylation in human colon cancer, suggesting a potential mechanism to be targeted for the prevention, treatment, and/or diagnosis of colon cancer. Advisors/Committee Members: Guo, Grace L. (advisor), Apte, Udayan (cmtemember), Hagenbuch, Bruno (cmtemember), Petroff, Brian K. (cmtemember), Zhong, Xiao-bo (cmtemember).

Subjects/Keywords: Cellular biology; Colon cancer; DNA methylation; Epigenetics; Farnesoid x receptor; Nuclear receptors

…Toxicology & Therapeutics at the University of Kansas Medical Center, particularly members of the…

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APA (6^th Edition):

Thomas, A. M. (2011). THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/8386

Chicago Manual of Style (16^th Edition):

Thomas, Ann M. “THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER.” 2011. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/8386.

MLA Handbook (7^th Edition):

Thomas, Ann M. “THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER.” 2011. Web. 19 Jan 2021.

Vancouver:

Thomas AM. THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER. [Internet] [Doctoral dissertation]. University of Kansas; 2011. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/8386.

Council of Science Editors:

Thomas AM. THE ROLE OF EPIGENETICS IN TRANSCRIPTIONAL REGULATION OF FXR AND SILENCING FXR EXPRESSION IN HUMAN COLON CANCER. [Doctoral Dissertation]. University of Kansas; 2011. Available from: http://hdl.handle.net/1808/8386

20. Shelton, Shary Nicole. MECHANISMS OF MITOCHONDRIA-MEDIATED APOPTOSIS INDUCED BY CYTOTOXIC STRESS.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/6761

► Defects within the apoptotic pathway are thought to contribute to tumorigenesis and therapeutic resistance. Although most cytotoxic anti-cancer drugs are thought to activate the mitochondria-mediated… (more)

Subjects/Keywords: Molecular biology; Apoptosis; DNA damage; Hsp90

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APA (6^th Edition):

Shelton, S. N. (2010). MECHANISMS OF MITOCHONDRIA-MEDIATED APOPTOSIS INDUCED BY CYTOTOXIC STRESS. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/6761

Chicago Manual of Style (16^th Edition):

Shelton, Shary Nicole. “MECHANISMS OF MITOCHONDRIA-MEDIATED APOPTOSIS INDUCED BY CYTOTOXIC STRESS.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/6761.

MLA Handbook (7^th Edition):

Shelton, Shary Nicole. “MECHANISMS OF MITOCHONDRIA-MEDIATED APOPTOSIS INDUCED BY CYTOTOXIC STRESS.” 2010. Web. 19 Jan 2021.

Vancouver:

Shelton SN. MECHANISMS OF MITOCHONDRIA-MEDIATED APOPTOSIS INDUCED BY CYTOTOXIC STRESS. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/6761.

Council of Science Editors:

Shelton SN. MECHANISMS OF MITOCHONDRIA-MEDIATED APOPTOSIS INDUCED BY CYTOTOXIC STRESS. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/6761

21. Araya, Juan Jose. Phase-Trafficking Methods in Natural Products, Modulators of Organic Anion Transporting Polypeptides from Rollinia emarginata, and Pregnane and Cardiac Glycosides from Asclepias spp.

Degree: PhD, Medicinal Chemistry, 2012, University of Kansas

URL: http://hdl.handle.net/1808/9993

► For decades, chemists and medicinal chemists have found in nature the source of inspiration for drug discovery and development. This work describes several aspects of… (more)

▼ For decades, chemists and medicinal chemists have found in nature the source of inspiration for drug discovery and development. This work describes several aspects of the interaction between the fields of natural products and medicinal chemistry, from isolation and characterization of bioactive molecules to semi-synthetic analogs preparation. A new phase-trafficking approach for acidic, basic, and neutral compounds separation from organic plant extracts was developed, validated and successfully applied to crude plant extracts. This new method could be applied to natural extracts of diverse origin in order to generate better quality samples for initial bioassays. Furthermore, this new catch-and-release methodology allowed the isolation and identification of three compounds new to the literature from the extensively studied ginger rhizomes. Using a more traditional bioassay guided fractionation, we have identified six small-molecules from Rollinia emarginata that modulate organic anion transporting polypeptide´s (OATPs) function. The results of this study show that diverse plant materials are a promising source for the isolation of OATP modulating compounds, and that a bioassay-guided approach can be used to efficiently identify selective OATP modulators. In addition, a 1H NMR-based metabolomic approach was used as a dereplication tool to study the effect of aqueous green tea extracts on OATP1B1-mediated uptake of estrone-3-sulfate. Our findings suggested that not only the gallate catechins were important for the observed uptake inhibition, but also compounds theogalline and 3-p-cumaroyl quinic acid could have been involved. A screening against breast cancer cell line Hs578T was conducted with ten plant species from the Asclepiadaceae family and, based on our findings, three plants were selected for detailed investigation: Asclepias verticillata, Asclepias syriaca, and Asclepias sullivantii. As a result, a total of 46 compounds were isolated and identified, half of which represented novel structures. The isolates showed a wide variety of structures including pregnane and cardiac glycosides, pentacyclic triterpenes, glycosylated flavonoids and lignans, among others. Furthermore, a group of cardiac glycosides were found to have strong cytotoxicity selected breast cancer cell lines. Finally, using a semi-synthetic approach, cardiac glycoside analogs with modifications in the butenolide ring were pursued in order to better understand their SAR. Starting from the commercially available trans-aldosterone, the cardiac glycoside core was built up using a microwave-promoted allylic oxidation using SeO2 (Riley oxidation). In addition, a microwave-promoted Miyaura-Suzuki cross-coupling was utilized to obtain the desired 17β-aryl analogs. Advisors/Committee Members: Timmermann, Barbara N (advisor), Mitscher, Lester A. (cmtemember), Prisinzano, Thomas E. (cmtemember), Kindscher, Kelly (cmtemember), Hagenbuch, Bruno (cmtemember).

Subjects/Keywords: Organic chemistry; Asclepias; Cardenolides; Natural products; Nmr; Oatp; Phase-trafficking

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APA (6^th Edition):

Araya, J. J. (2012). Phase-Trafficking Methods in Natural Products, Modulators of Organic Anion Transporting Polypeptides from Rollinia emarginata, and Pregnane and Cardiac Glycosides from Asclepias spp. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/9993

Chicago Manual of Style (16^th Edition):

Araya, Juan Jose. “Phase-Trafficking Methods in Natural Products, Modulators of Organic Anion Transporting Polypeptides from Rollinia emarginata, and Pregnane and Cardiac Glycosides from Asclepias spp.” 2012. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/9993.

MLA Handbook (7^th Edition):

Araya, Juan Jose. “Phase-Trafficking Methods in Natural Products, Modulators of Organic Anion Transporting Polypeptides from Rollinia emarginata, and Pregnane and Cardiac Glycosides from Asclepias spp.” 2012. Web. 19 Jan 2021.

Vancouver:

Araya JJ. Phase-Trafficking Methods in Natural Products, Modulators of Organic Anion Transporting Polypeptides from Rollinia emarginata, and Pregnane and Cardiac Glycosides from Asclepias spp. [Internet] [Doctoral dissertation]. University of Kansas; 2012. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/9993.

Council of Science Editors:

Araya JJ. Phase-Trafficking Methods in Natural Products, Modulators of Organic Anion Transporting Polypeptides from Rollinia emarginata, and Pregnane and Cardiac Glycosides from Asclepias spp. [Doctoral Dissertation]. University of Kansas; 2012. Available from: http://hdl.handle.net/1808/9993

22. Wu, Kai Connie. THE ROLE OF NRF2 IN PREVENTING OXIDATIVE/ELECTROPHILIC STRESS-INDUCED LIVER INJURY.

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

URL: http://hdl.handle.net/1808/10289

► Redox maintenance is critical for all biological species. Amplification of mechanisms that reduces oxidative/electrophilic stress promotes health and extends life. Nuclear factor, erythroid derived 2,… (more)

▼ Redox maintenance is critical for all biological species. Amplification of mechanisms that reduces oxidative/electrophilic stress promotes health and extends life. Nuclear factor, erythroid derived 2, like 2 (Nrf2) is a master regulator of biochemical mechanisms that respond to oxidative/electrophilic stress. Under basal conditions, Nrf2 is held in an inactive state in the cytoplasm by binding to the cytoskeletal anchoring protein Kelch-like ECH-associated protein 1 (Keap1). Upon generation of oxidative/electrophilic stress, Nrf2 is released from Keap1 and translocates to the nucleus, where it promotes transcription of a battery of cytoprotective genes. The antioxidative role of Nrf2 has been extensively studied for more than ten years, but the global Nrf2 target genes in liver still remain unknown. The present dissertation utilizes a Nrf2 "gene dose-response" model to genetically modulate the levels of Nrf2 in mouse liver, where the transcription profiles in livers of mice with graded Nrf2 activation were correlated with activation of Nrf2-target genes. Thus, the Nrf2-target genes in mouse liver were investigated systematically. Pathway analyses indicate that genes induced by Nrf2 are involved in glutathione synthesis, oxidation/reduction using NADPH as the co-factor, and xenobiotic metabolism. Moreover, mRNA of genes involved in the pentose phosphate pathway and malic enzyme levels had a clear dose-dependent correlation to active levels of Nrf2, indicating that Nrf2 promotes NADPH generation. Among genes suppressed by Nrf2, the majority are involved in lipid synthesis and fatty-acid desaturation. Thus, Nrf2 promotes generation of NADPH, and reduces fatty acid synthesis and desaturation, contributing factors towards protecting liver against environmental oxidative/electrophilic stress. The mRNA abundance of 124 drug processing genes in the Nrf2 "gene dose-response" model was also determined in this dissertation. The results indicate that Nrf2 facilitates electrophile detoxification through inducing non P-450 phase-I enzymes that reduce electrophiles, Gsts that conjugate electrophiles, and efflux transporters that excrete electrophile-GSH conjugates out of cells. In addition to the assessment of the effect of Nrf2 on the global gene transcription profiles in mouse liver, the function of Nrf2 in vivo was examined by testing whether Nrf2 activation protects against chemical-induced oxidative stress and subsequent liver injury in mice. Oxidative stress and lipid accumulation play important roles in ethanol-induced liver injury. Ethanol increased serum ALT and LDH activities in Nrf2-null mice and wild-type mice, but not in Nrf2-enhanced mice, indicating that Nrf2-enhanced mice are resistant to ethanol toxicity. Ethanol increased free fatty acids in livers of Nrf2-null mice, and this increase was blunted in Nrf2-enhanced mice. Mechanistic studies show that Nrf2 prevents ethanol-induced oxidative stress through inducing cytoprotective genes including Nqo1 and Gclc, and prevents accumulation of free fatty acids in liver by… Advisors/Committee Members: Klaassen, Curtis D. (advisor), Weinman, Steven A. (cmtemember), Pazdernik, Thomas L. (cmtemember), Kasturi, Partha (cmtemember), Hagenbuch, Bruno (cmtemember).

Subjects/Keywords: Toxicology; High throughput screening; Liver; Microarray; Nrf2; Oxidative stress

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APA (6^th Edition):

Wu, K. C. (2012). THE ROLE OF NRF2 IN PREVENTING OXIDATIVE/ELECTROPHILIC STRESS-INDUCED LIVER INJURY. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/10289

Chicago Manual of Style (16^th Edition):

Wu, Kai Connie. “THE ROLE OF NRF2 IN PREVENTING OXIDATIVE/ELECTROPHILIC STRESS-INDUCED LIVER INJURY.” 2012. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/10289.

MLA Handbook (7^th Edition):

Wu, Kai Connie. “THE ROLE OF NRF2 IN PREVENTING OXIDATIVE/ELECTROPHILIC STRESS-INDUCED LIVER INJURY.” 2012. Web. 19 Jan 2021.

Vancouver:

Wu KC. THE ROLE OF NRF2 IN PREVENTING OXIDATIVE/ELECTROPHILIC STRESS-INDUCED LIVER INJURY. [Internet] [Doctoral dissertation]. University of Kansas; 2012. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/10289.

Council of Science Editors:

Wu KC. THE ROLE OF NRF2 IN PREVENTING OXIDATIVE/ELECTROPHILIC STRESS-INDUCED LIVER INJURY. [Doctoral Dissertation]. University of Kansas; 2012. Available from: http://hdl.handle.net/1808/10289

23. Hays, Amanda Lynne. Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy.

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

URL: http://hdl.handle.net/1808/11446

► Organic Anion Transporting Polypeptides (OATPs) are multispecific transport proteins that mediate the uptake of numerous endogenous and exogenous compounds into cells. Recently, OATPs have been… (more)

▼ Organic Anion Transporting Polypeptides (OATPs) are multispecific transport proteins that mediate the uptake of numerous endogenous and exogenous compounds into cells. Recently, OATPs have been shown to have altered expression in cancer tissue compared to their normal expression profiles. It has been proposed that OATPs can be targeted to improve cancer therapeutics. Therefore, I tested the hypothesis that expression of OATPs in cancer combined with their ability to transport cytotoxic anticancer drugs makes them potential targets for improving cancer diagnosis and therapy. The hypothesis was tested via the following specific aims: 1) to identify and characterize OATP expression in cancer, 2) to identify novel anticancer drug substrates of OATPs, and 3) to identify novel cytotoxic compounds from plant extracts that are substrates of OATPs and can be developed into anticancer drugs that target OATP-expressing cancers. In the first specific aim, OATPs expressed in pancreatic cancer were identified by immunohistochemical staining of pancreatic cancer tissue specimens. Completion of this specific aim identified four major OATPs expressed in pancreatic adenocarcinomas. Additionally, OATP1B3 expression was observed to be highest in low stage adenocarcinoma and absent in metastatic tissue. These results demonstrate that OATP1B3 may serve as a diagnostic marker and/or therapeutic target in early stage adenocarcinomas. In specific aim two, novel anticancer drug substrates of OATP1B3 were identified by screening the NCI/DTP oncology drug set containing all of the FDA approved chemotherapy drugs. In this study, I determined the effect of the anticancer drugs on transport and cell viability of OATP1B3-expressing cells. Finally, I demonstrated that the anticancer drugs etoposide, oxaliplatin and plicamycin are substrates of OATP1B3. These results suggest that the mentioned cytotoxic anticancer drugs could potentially be used to treat OATP1B3-expressing cancers. In the last specific aim, Kansas plant extracts were screened using bioassay guided fractionation and cell viability assays to isolate novel cytotoxic compounds that are substrates of OATP1B3. Given that these novel plant compounds are cytotoxic and are also transported by OATP1B3 suggests that they can be used for lead optimization studies to develop new anticancer drug entities. This dissertation demonstrates that OATP1B3 is a potential target for mechanisms of OATP-mediated anticancer therapy. Ultimately, this knowledge can be used to utilize OATP1B3 expression in cancer as a diagnostic marker, as well as a target for cytotoxic anticancer drug therapies. Advisors/Committee Members: Hagenbuch, Bruno (advisor), Apte, Udayan (cmtemember), Geiger, Paige C (cmtemember), Reed, Gregory A. (cmtemember), Zhu, Bao-Ting (cmtemember).

Subjects/Keywords: Pharmacology; Cancer; Oatp; Transporters

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APA (6^th Edition):

Hays, A. L. (2012). Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/11446

Chicago Manual of Style (16^th Edition):

Hays, Amanda Lynne. “Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy.” 2012. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/11446.

MLA Handbook (7^th Edition):

Hays, Amanda Lynne. “Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy.” 2012. Web. 19 Jan 2021.

Vancouver:

Hays AL. Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy. [Internet] [Doctoral dissertation]. University of Kansas; 2012. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/11446.

Council of Science Editors:

Hays AL. Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy. [Doctoral Dissertation]. University of Kansas; 2012. Available from: http://hdl.handle.net/1808/11446

University of Kansas

24. Cui, Yue. DEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/6777

► Despite the recent progress in understanding the expression patterns and regulatory mechanisms of drug-processing genes, namely phase-I and -II drug metabolizing enzymes and transporters in… (more)

▼ Despite the recent progress in understanding the expression patterns and regulatory mechanisms of drug-processing genes, namely phase-I and -II drug metabolizing enzymes and transporters in adults, very little is known of the alterations of these genes during liver development. Therefore, newborns and children are potentially at a higher risk of adverse drug reactions. The purpose of my dissertation is to characterize the expression and regulatory mechanisms of the drug-processing genes during postnatal liver maturation. The present study integrated various research technologies, including genetically-engineered mice, messenger RNA and protein assays, ChIP-on-chip, ChIP-Seq, transcription-factor binding assays, LC-MS/MS, and bioinformatics analysis. Cluster analysis demonstrated that the ontogenic expression of 82 drug-processing genes separate into 4 distinct patterns: perinatal enriched, early-adolescent enriched, late-adolescent enriched, and adult enriched. Critical nuclear receptors, including the xenobiotic sensor pregnane X receptor (PXR, N1I2), and the bile-acid sensor farnesoid X receptor (FXR, NR1H4), are crucial in regulating the expression of drug-processing genes during liver development. Initiation of bile-acid signaling, mediated largely via FXR, is a hallmark of the neonatal induction of major liver transporters involved in the enterohepatic circulation of bile acids, whereas PXR is more important for the induction of xenobiotic-processing genes in adolescent and adult period. Because the accessibility of transcription factors to the target genes is determined by chromatin epigenetic mechanisms, I have also determined the correlations between the expression of drug-processing genes and distinct chromatin epigenetic marks, and identified that histone H3 lysine 4 di-methylation (H3K4Me2) appeared to be the choice of nature to induce numerous drug-processing genes during postnatal liver development. In conclusion, in the present dissertation, I have performed a systemic characterization of critical drug-processing genes and transcription factors during postnatal liver maturation. I have demonstrated that the developmental regulation of drug metabolism and transport is a sequential event associated with changes of chromatin epigenetic signatures, which set a permissive environment for ligand-activated nuclear receptors to gain access to the target genes prior to transcription initiation. The current work has generated basic knowledge that will serve as a foundation for further understanding of pediatric pharmacology and toxicology in humans. Advisors/Committee Members: Klaassen, Curtis D. (advisor), Wan, Yu-Jui Yvonne (cmtemember), Hagenbuch, Bruno (cmtemember), Guo, Grace (cmtemember), Christenson, Lane (cmtemember).

Subjects/Keywords: Health sciences; Toxicology; Pharmacology; Molecular biology; Bile acids; Drug metabolism; Epigenetics; Liver development; Nuclear receptors; Transporters

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APA (6^th Edition):

Cui, Y. (2010). DEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/6777

Chicago Manual of Style (16^th Edition):

Cui, Yue. “DEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/6777.

MLA Handbook (7^th Edition):

Cui, Yue. “DEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER.” 2010. Web. 19 Jan 2021.

Vancouver:

Cui Y. DEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/6777.

Council of Science Editors:

Cui Y. DEVELOPMENTAL REGULATION OF THE DRUG-PROCESSING GENOME IN MOUSE LIVER. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/6777

University of Kansas

25. Pacyniak, Erik Kristofer. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/7717

► Polybrominated diphenyl ethers (PBDEs) were introduced in the late 1970's as additive flame retardants incorporated into textiles, electronics, plastics and furniture. Although 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209)… (more)

▼ Polybrominated diphenyl ethers (PBDEs) were introduced in the late 1970's as additive flame retardants incorporated into textiles, electronics, plastics and furniture. Although 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209) is the only congener currently on the market, 2,2`,4,4`-tetrabromodiphenyl ether (BDE47), 2,2`,4,4`,5-pentabromodiphenyl ether (BDE99), and 2,2`,4,4`,5,5`-hexabromodiphenyl ether (BDE153) are the predominant congeners detected in human and wildlife samples. Upon exposure, PBDEs enter the liver where they are biotransformed to potentially toxic metabolites. Although the human liver burden of PBDEs is not clear, the presence of PBDEs in human liver is particularly alarming because it has been demonstrated in rodents that hydroxylated metabolites may play a pivotal role in PBDE-mediated toxicity. The mechanism by which PBDEs enter the liver was not known. However, due to their large molecular weights (MWs ~485 to 1000 Da), they were not likely to enter hepatocytes by simple diffusion. Organic anion transporting polypeptides (OATPs: human; Oatps: rodents) are responsible for hepatic uptake of a variety of amphipathic compounds of MWs larger than 350 Da. Therefore, I tested the hypothesis that OATPs/Oatps expressed in human and mouse hepatocytes are responsible for the uptake of PBDE congeners 47, 99, and 153 by using Chinese hamster ovary (CHO) cell lines expressing OATP1B1, OATP1B3, or OATP2B1 and Human Embryonic Kidney 293 (HEK293) cells transiently expressing Oatp1a1, Oatp1a4, Oatp1b2, or Oatp2b1. Direct uptake studies illustrated that PBDE congeners are substrates of human and mouse hepatic OATPs/Oatps, except for Oatp1a1. Detailed kinetic analysis revealed that OATP1B1, OATP1B3, Oatp1a4, and Oatp1b2 transport BDE47 with the highest affinity followed by BDE99 and BDE153. However, both OATP2B1 and Oatp2b1 transported all three congeners with similar affinities. The importance of hepatic Oatps for the accumulation of BDE47 in liver was confirmed using Oatp1a4- and Oatp1b2-null mice. These results clearly suggest that uptake of PBDEs via these OATPs/Oatps are responsible for liver-specific accumulation of PBDEs. In mouse liver, PBDEs induce drug metabolizing enzymes, namely cytochrome P450s (Cyps). However, the molecular mechanisms underlying this induction was unknown. Cyp2b10 and 3a11 are target genes of the xenobiotic nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both of which are responsible for mediating induction of Cyp2b10 and Cyp3a11, respectively. I hypothesized that PBDE congeners are CAR and/or PXR activators. Using reporter-gene luciferase assays I showed that BDE47, BDE99 and BDE209 activate human and mouse CAR and PXR in a concentration-dependent manner. Furthermore, induction of Cyp2b10 and Cyp3a11 was markedly suppressed in CAR- and PXR-null mice, respectively, indicating that PBDE congeners activate these receptors in vivo. BDE47 and BDE99, the primary congeners detected in humans in the United States, are capable of inducing… Advisors/Committee Members: Guo, Grace L. (advisor), Hagenbuch, Bruno (cmtemember), Klaassen, Curtis D. (cmtemember), Reed, Gregory A. (cmtemember), Petroff, Brian K. (cmtemember).

Subjects/Keywords: Toxicology; Constitutive androstane receptor; Nuclear receptors; Organic anion transporting polypeptide; Polybrominated diphenyl ethers; Pregnane x receptor

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APA (6^th Edition):

Pacyniak, E. K. (2010). Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/7717

Chicago Manual of Style (16^th Edition):

Pacyniak, Erik Kristofer. “Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/7717.

MLA Handbook (7^th Edition):

Pacyniak, Erik Kristofer. “Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.” 2010. Web. 19 Jan 2021.

Vancouver:

Pacyniak EK. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/7717.

Council of Science Editors:

Pacyniak EK. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/7717

University of Kansas

26. Wang, Pan. Computational Molecular Modeling Studies of the Interactions of Estrogens with Their Receptors and Intracellular Estrogen Binding Protein PDIp.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/7432

► The endogenous estrogens are vitally-important female sex hormones with diverse biological functions. Disruption of their actions contributes to the pathogenesis of a number of disease… (more)

Subjects/Keywords: Pharmacology; Antiestrogen; Estrogen; Estrogen receptor; Molecular docking; Molecular modeling; Pdip

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APA (6^th Edition):

Wang, P. (2010). Computational Molecular Modeling Studies of the Interactions of Estrogens with Their Receptors and Intracellular Estrogen Binding Protein PDIp. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/7432

Chicago Manual of Style (16^th Edition):

Wang, Pan. “Computational Molecular Modeling Studies of the Interactions of Estrogens with Their Receptors and Intracellular Estrogen Binding Protein PDIp.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/7432.

MLA Handbook (7^th Edition):

Wang, Pan. “Computational Molecular Modeling Studies of the Interactions of Estrogens with Their Receptors and Intracellular Estrogen Binding Protein PDIp.” 2010. Web. 19 Jan 2021.

Vancouver:

Wang P. Computational Molecular Modeling Studies of the Interactions of Estrogens with Their Receptors and Intracellular Estrogen Binding Protein PDIp. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/7432.

Council of Science Editors:

Wang P. Computational Molecular Modeling Studies of the Interactions of Estrogens with Their Receptors and Intracellular Estrogen Binding Protein PDIp. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/7432

University of Kansas

27. Song, Peizhen. EFFECT OF BILE ACID FEEDING AND SEQUESTRATION ON LIVER BILE ACID COMPOSITION AND GENE REGULATION IN MICE.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/7756

► The dissertation investigates the non-hepatotoxic doses of five bile acids (BAs) in the feed of mice, as well as adaptations in the expression of genes… (more)

▼ The dissertation investigates the non-hepatotoxic doses of five bile acids (BAs) in the feed of mice, as well as adaptations in the expression of genes involved in BA homeostasis and the possible roles of FXR-mediated signaling in regulating these genes. Mice were fed four main BAs, cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA), and the therapeutic BA ursodeoxycholic acid (UDCA), at various concentrations in their diets (0.01, 0.03, 0.1, 0.3, 1.0, or 3.0%), as well as the BA sequestrant cholestyramine (resin) at 2% in their diets, for one week. Subsequently, serum alanine aminotransferase (ALT), serum and hepatic BA concentrations, as well as mRNAs of genes involved in BA homeostasis were quantified. The data showed: 1) LCA produced hepatotoxicity at 0.03%, indicated by increases in serum ALT and serum BA concentration, as did DCA at 0.1%, and CDCA and CA at 0.3% in the diet. UDCA at 0.3% in the diet might be hepatotoxic because the serum BA concentration was increased but the serum ALT did not increase. 2) Feeding BAs at hepatotoxic doses altered liver BA composition. 3) The mRNA of SHP and Cyp7a1 in the liver was increased by all doses of BAs. In contrast, BA regulation of the mRNA of the hepatic Cyp8b1 and the ileal Fgf15 are BA species dependent: CA and DCA at all doses increased Fgf15 and decreased Cyp8b1, whereas, CDCA and LCA at high doses increased Fgf15 and decreased Cyp8b1 mRNA. 4) Feeding resin increased the mRNA Cyp7a1 and Cyp8b1 in the liver and Fgf15 in the ileum. In conclusion, my dissertation demonstrates the non-hepatotoxic doses of individual BAs are as follows: 0.1% or lower in the diets for CA, CDCA, and UDCA, 0.03% for DCA, and 0.01% or lower for LCA. In addition, the altered liver BA composition after non-hepatotoxic doses of BA-feeding are able to trigger the hepatic FXR-SHP and the ileal FXR-Fgf15 signaling pathways, which coordinately regulate Cyp7a1 and Cyp8b1. Moreover, the the decreased expression of the ileal Fgf15 after feeding resin caused increases in mRNA expression of CYp7a1 and Cyp8b1. Advisors/Committee Members: Klaassen, Curtis D. (advisor), Copple, Bryan (cmtemember), Guo, Grace (cmtemember), Hagenbuch, Bruno (cmtemember), Staudinger, Jeff L. (cmtemember).

Subjects/Keywords: Toxicology; Pathology; Bile acids; Cholestyramine resin; Cyp7a1; Cyp8b1; Fgf15; Fxr

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

APA (6^th Edition):

Song, P. (2010). EFFECT OF BILE ACID FEEDING AND SEQUESTRATION ON LIVER BILE ACID COMPOSITION AND GENE REGULATION IN MICE. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/7756

Chicago Manual of Style (16^th Edition):

Song, Peizhen. “EFFECT OF BILE ACID FEEDING AND SEQUESTRATION ON LIVER BILE ACID COMPOSITION AND GENE REGULATION IN MICE.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/7756.

MLA Handbook (7^th Edition):

Song, Peizhen. “EFFECT OF BILE ACID FEEDING AND SEQUESTRATION ON LIVER BILE ACID COMPOSITION AND GENE REGULATION IN MICE.” 2010. Web. 19 Jan 2021.

Vancouver:

Song P. EFFECT OF BILE ACID FEEDING AND SEQUESTRATION ON LIVER BILE ACID COMPOSITION AND GENE REGULATION IN MICE. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/7756.

Council of Science Editors:

Song P. EFFECT OF BILE ACID FEEDING AND SEQUESTRATION ON LIVER BILE ACID COMPOSITION AND GENE REGULATION IN MICE. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/7756

University of Kansas

28. Bu, Pengli. RETINOID-INDUCED APOPTOSIS AND PROLIFERATION OF HEPATOCYTES ARE MEDIATED BY DISTINCT NUCLEAR RECEPTORS.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2009, University of Kansas

URL: http://hdl.handle.net/1808/5385

► Retinoids, derivatives of vitamin A, are important signaling molecules regulating cellular homeostasis including differentiation, apoptosis, and proliferation. In this dissertation, we examined the versatile effects… (more)

Subjects/Keywords: Health sciences; Toxicology; Pharmacology; Apoptosis; Hepatocyte; Nuclear receptors; Proliferation; Retinoid

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

APA (6^th Edition):

Bu, P. (2009). RETINOID-INDUCED APOPTOSIS AND PROLIFERATION OF HEPATOCYTES ARE MEDIATED BY DISTINCT NUCLEAR RECEPTORS. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/5385

Chicago Manual of Style (16^th Edition):

Bu, Pengli. “RETINOID-INDUCED APOPTOSIS AND PROLIFERATION OF HEPATOCYTES ARE MEDIATED BY DISTINCT NUCLEAR RECEPTORS.” 2009. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/5385.

MLA Handbook (7^th Edition):

Bu, Pengli. “RETINOID-INDUCED APOPTOSIS AND PROLIFERATION OF HEPATOCYTES ARE MEDIATED BY DISTINCT NUCLEAR RECEPTORS.” 2009. Web. 19 Jan 2021.

Vancouver:

Bu P. RETINOID-INDUCED APOPTOSIS AND PROLIFERATION OF HEPATOCYTES ARE MEDIATED BY DISTINCT NUCLEAR RECEPTORS. [Internet] [Doctoral dissertation]. University of Kansas; 2009. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/5385.

Council of Science Editors:

Bu P. RETINOID-INDUCED APOPTOSIS AND PROLIFERATION OF HEPATOCYTES ARE MEDIATED BY DISTINCT NUCLEAR RECEPTORS. [Doctoral Dissertation]. University of Kansas; 2009. Available from: http://hdl.handle.net/1808/5385

University of Kansas

29. Weaver, Yi Miao. STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/7394

► The organic anion transporting polypeptides (human: OATP; other: Oatp) form a mammalian transporter superfamily that mediates the transport of structurally unrelated compounds across the cell… (more)

▼ The organic anion transporting polypeptides (human: OATP; other: Oatp) form a mammalian transporter superfamily that mediates the transport of structurally unrelated compounds across the cell membrane. Members in this superfamily participate in the absorption, distribution and excretion of many endogenous and exogenous substances including a number of medications and environmental toxicants. Polymorphisms of OATPs have been shown clinically to give rise to inter-individual variabilities of drug efficacy and/or toxicity. Furthermore, as multi-specific transporters, they are potential sites for drug-drug interactions. Therefore, understanding the mechanism of OATP/Oatp mediated transport of endo- and xenobiotics will not only help to improve drug efficacy but also to improve the prediction and prevention of toxicity. The overall goal of this dissertation is identifying key amino acids that may play an important role in OATP/Oatp-mediated transport and investigating the spatial size of the substrate binding/translocation pocket. In this dissertation, I defended three specific aims. In the first specific aim, I evaluated the hypothesis that conserved positively charged amino acids play important roles in OATP1B1 transport function. To address this aim, site-directed mutagenesis was employed and the mutants of several conserved positively charged amino acids were studied. The two extracellular amino acids R57 and K361 were found to be important in OATP1B1 mediated transport of estradiol-17β-glucuronide, estrone-3-sulfate and BSP. In the second specific aim, I evaluated the hypothesis that quantifying transport activities of different substrates mediated by chimeras between rat Oatp1a1 and Oatp1a4 in combination with site-directed mutagenesis should allow us to identify regions and/or individual amino acids that are important for Oatp1a4-mediated substrate recognition and/or transport. The effects of chimeric proteins on transport activity were substrate dependent. Extracellular loop 4 and transmembrane domain 8 were identified to be important in transport of digoxin, taurocholate and estradiol-17β-glucuronide. The C-terminal half of Oatp1a4 and Oatp1a1 was found to be important for BSP transport and the interactions between the N-terminal half and the C-terminal half of Oatp1a4 is essential for DPDPE transport. In the third specific aim, I evaluated the hypothesis that different rat renal organic anion transporters of the Oat and Oatp families selectively transport perfluorinated carboxylates (PFCAs) depending on the chain lengths. The purpose of this study was to determine the substrate size selectivity of Oats and Oatp1a1. To address this aim, the inhibitory effects of PFCAs with chain length from C2 to C18 on transport of model substrates by rat Oat1, Oat2, Oat3, Urat1 and Oatp1a1 was quantified. Furthermore, direct uptake of the best inhibitors was characterized. The best substrates for Oats were C7 and C8, whereas Oatp1a1 transported longer PFCAs such as C9 and C10 better than C8 and C7. Altogether, this dissertation… Advisors/Committee Members: Hagenbuch, Bruno (advisor), Klaassen, Curtis D. (cmtemember), Reed, Gregory A. (cmtemember), Guo, Grace (cmtemember), Blanco, Gustavo (cmtemember).

Subjects/Keywords: Health sciences; Pharmacology; Biology; Physiology; Oatp; Organic anion; Perfluoronated carboxylates; Pfca; Structure; Transporters

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

APA (6^th Edition):

Weaver, Y. M. (2010). STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/7394

Chicago Manual of Style (16^th Edition):

Weaver, Yi Miao. “STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 19, 2021. http://hdl.handle.net/1808/7394.

MLA Handbook (7^th Edition):

Weaver, Yi Miao. “STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT.” 2010. Web. 19 Jan 2021.

Vancouver:

Weaver YM. STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 19]. Available from: http://hdl.handle.net/1808/7394.

Council of Science Editors:

Weaver YM. STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/7394

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