+publisher:"University of Kansas" +contributor:("Petroff, Brian K.")

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

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 23, 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. 23 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 23]. 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

2. Fitzgerald, Jonathan Browning. Novel Direct Targets and Functional Roles for MicroRNA-21 in Granulosa Cells and Human Uterine Leiomyomas.

Degree: PhD, Molecular & Integrative Physiology, 2013, University of Kansas

URL: http://hdl.handle.net/1808/12278

► MicroRNA-21 (miR-21) is important for maintaining optimal ovulation rates and granulosa cell viability. It is also upregulated in human uterine leiomyomas (ULMs), a disease characterized… (more)

▼ MicroRNA-21 (miR-21) is important for maintaining optimal ovulation rates and granulosa cell viability. It is also upregulated in human uterine leiomyomas (ULMs), a disease characterized by the presence of benign tumors on the myometrium. The primary objective of this thesis was to identify miR-21 direct targets in granulosa cells that mediate its important ovarian functions. The secondary objective was to elucidate the role of miR-21 in ULMs. Gene expression and bioinformatic analysis performed on granulosa cells after miR-21 inhibition identified many potential miR-21 direct targets. Luciferase assays revealed that miR-21 regulates the 3fUntranslated Region (3fUTR) of apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (Apobec3), intestinal-specific homeobox (ISX) and ubiquitin-specific protease 30 (USP30). Further research of ISX revealed that miR-21 binds to its 3fUTR and over expression of miR-21 causes inhibition of ISX protein levels. Quantitative RT-PCR and western analysis revealed that ISX regulates scavenger receptor class B type 1 (SRB1) fÀ,fÀ-carotene 15,15Oe-monooxygenase 1 (BCMO1) and retinoic acid receptor f¿ (RARf¿) in granulosa cells, genes known to be involved in steriodogenesis, embryogenesis and meiotic resumption in the ovary, respectively. Therefore, miR-21 may be regulating these functions through directly targeting ISX in granulosa cells. Investigation of miR-21 in UtM and UtLM cell lines (cell lines derived from myometrial and leiomyoma tissue, respectively) showed that miR-21 inhibits phosphorylation of elongation factor 2 and prevents expression of cleaved caspase 3 in both cell lines; findings which suggest that miR-21 is important for preventing cell death and maintaining cellular translation in these cell lines. Further research showed that miR-21 inhibits expression of programmed cell death 4 (PDCD-4). Expression analysis of PDCD-4 showed that it is highly expressed in ULM tissue when compared to paired healthy myometrial tissue. Since PDCD-4 is a known tumor suppressor that is suppressed in tumors, this finding indicates that PDCD-4 is playing an alternative role in ULMs compared to other tumorigenic tissue. Since miR-21 is also overexpressed in ULMs, miR-21 is excluded as a means of post-transcriptional gene control that gives rise to PDCD-4 induction in ULMs. Together these studies have identified novel direct targets for miR-21 in granulosa cells and implicated one of miR-21fs most well-studied direct targets, PDCD-4 in a novel functional role in ULMs. Advisors/Committee Members: Christenson, Lane K. (advisor), Wolfe, Michael W. (cmtemember), Petroff, Brian K. (cmtemember), Vivian, Jay L. (cmtemember), Chennathukuzhi, Vargheese M. (cmtemember), Kinsey, William H. (cmtemember).

Subjects/Keywords: Biology; Molecular biology; Physiology; Granulosa cells; Human uterine leiomyomas; MicroRNA; Ovary

…University of Kansas Medical Center. After sacrifice ovaries were removed immediately and placed in…

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

APA (6^th Edition):

Fitzgerald, J. B. (2013). Novel Direct Targets and Functional Roles for MicroRNA-21 in Granulosa Cells and Human Uterine Leiomyomas. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/12278

Chicago Manual of Style (16^th Edition):

Fitzgerald, Jonathan Browning. “Novel Direct Targets and Functional Roles for MicroRNA-21 in Granulosa Cells and Human Uterine Leiomyomas.” 2013. Doctoral Dissertation, University of Kansas. Accessed January 23, 2021. http://hdl.handle.net/1808/12278.

MLA Handbook (7^th Edition):

Fitzgerald, Jonathan Browning. “Novel Direct Targets and Functional Roles for MicroRNA-21 in Granulosa Cells and Human Uterine Leiomyomas.” 2013. Web. 23 Jan 2021.

Vancouver:

Fitzgerald JB. Novel Direct Targets and Functional Roles for MicroRNA-21 in Granulosa Cells and Human Uterine Leiomyomas. [Internet] [Doctoral dissertation]. University of Kansas; 2013. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1808/12278.

Council of Science Editors:

Fitzgerald JB. Novel Direct Targets and Functional Roles for MicroRNA-21 in Granulosa Cells and Human Uterine Leiomyomas. [Doctoral Dissertation]. University of Kansas; 2013. Available from: http://hdl.handle.net/1808/12278

University of Kansas

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

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 23, 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. 23 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 23]. 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

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

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 23, 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. 23 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 23]. 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

5. Ting, Alison. Novel Strategies in Cancer Prevention and Fertility Preservation with Tamoxifen.

Degree: PhD, Molecular & Integrative Physiology, 2009, University of Kansas

URL: http://hdl.handle.net/1808/5389

► Women at high risk for breast cancer are often also at high risk for ovarian cancer, reflecting similar risk factors and suggesting intertwined disease pathways… (more)

▼ Women at high risk for breast cancer are often also at high risk for ovarian cancer, reflecting similar risk factors and suggesting intertwined disease pathways and common prevention targets. A novel strategy to overcome obstacles in preventing ovarian neoplasia (low incidence, lack of specific disease markers, and difficulties in tissue sampling), the deadliest gynecologic cancer, may be to develop a prevention strategy that targets breast and ovarian cancer simultaneously. Tamoxifen, a selective estrogen receptor modulator, reduces hormone responsive breast cancer risk by 50% but its effects on risk of ovarian cancer, also hormonal responsive, are unclear. The goals of this work were to 1) develop and characterize a preclinical model of concurrent breast and ovarian cancer and 2) use this dual cancer model to examine the efficacy of tamoxifen to prevent both breast and ovarian cancer. Mammary carcinogens [7,12-dimethylbenz[α]anthracene (DMBA), N-methyl-N-nitrosourea and estradiol (Ey2)] were tested separately in combination with local ovarian DMBA administration to determine the best combined treatment to induce mammary and ovarian cancer concurrently and effectively in the rat. Results showed that systemic Ey2 and ovarian DMBA promoted the highest incidence of dysplasia in the mammary gland and ovary and elevated levels of mammary Ki-67 and cyclooxygenase 2 (COX-2) mimicking the human disease. Next, the ability of tamoxifen to prevent mammary and ovarian cancer simultaneously was evaluated. Tamoxifen which inhibited mammary carcinogenesis and normalized levels of Ki-67 and COX-2, had no effect on (neither accelerated nor inhibited) ovarian cancer progression. In addition, carcinogen treatment increased levels of stem cell markers, Oct-4 and aldehyde dehydrogenase-1, in the mammary gland; interestingly, this expansion was not reversed by tamoxifen. Intriguingly, while examining ovaries from this study, we serendipitously discovered an apparent protective effect of tamoxifen against DMBA-induced follicular destruction and this effect was further investigated. Chemotherapy and environmental toxicants (e.g. DMBA) deplete ovarian follicles and often lead to accelerated ovarian aging and premature ovarian failure; however, there is no established treatment that can protect the ovary from these toxic insults. In vivo, rats were treated with tamoxifen and DMBA or cyclophosphamide (the most ovotoxic chemotherapy) and total numbers of follicles in the ovary were determined. In vitro, ovarian organ culture and oocyte culture were carried out to examine local effects of tamoxifen on DMBA-induced follicle loss and doxorubicin-induced oocyte fragmentation, respectively. We demonstrated for the first time that tamoxifen protects ovarian follicles against not only DMBA- but also chemotherapy (cyclophosphamide and doxorubicin)-induced ovarian damage. Clinically, tamoxifen has already been tested for safe use as an adjuvant therapy for several cancers; therefore, if translated into clinical use, these results may have immediate… Advisors/Committee Members: Petroff, Brian K (advisor), Christenson, Lane K. (cmtemember), Guo, Grace (cmtemember), Li, Sara (cmtemember), Kimler, Bruce (cmtemember).

Subjects/Keywords: Health sciences; Oncology; Biology; Physiology; Animal model; Breast cancer; Cancer prevention; Fertility preservation; Ovarian cancer; Tamoxifen

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

APA (6^th Edition):

Ting, A. (2009). Novel Strategies in Cancer Prevention and Fertility Preservation with Tamoxifen. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/5389

Chicago Manual of Style (16^th Edition):

Ting, Alison. “Novel Strategies in Cancer Prevention and Fertility Preservation with Tamoxifen.” 2009. Doctoral Dissertation, University of Kansas. Accessed January 23, 2021. http://hdl.handle.net/1808/5389.

MLA Handbook (7^th Edition):

Ting, Alison. “Novel Strategies in Cancer Prevention and Fertility Preservation with Tamoxifen.” 2009. Web. 23 Jan 2021.

Vancouver:

Ting A. Novel Strategies in Cancer Prevention and Fertility Preservation with Tamoxifen. [Internet] [Doctoral dissertation]. University of Kansas; 2009. [cited 2021 Jan 23]. Available from: http://hdl.handle.net/1808/5389.

Council of Science Editors:

Ting A. Novel Strategies in Cancer Prevention and Fertility Preservation with Tamoxifen. [Doctoral Dissertation]. University of Kansas; 2009. Available from: http://hdl.handle.net/1808/5389

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