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You searched for +publisher:"University of Arizona" +contributor:("Maher, Jonathan"). Showing records 1 – 2 of 2 total matches.

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University of Arizona

1. Kerins, Michael John. Ironing Out Roles and Regulation of NRF2 in a Hereditary Cancer Syndrome .

Degree: 2019, University of Arizona

The deadly kidney cancers associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) show activation of the nuclear factor (erythroid 2)-like 2 (NFE2L2, NRF2) transcription factor. NRF2 activation causes chemoresistance and limits therapeutic efficacy. However, clear mechanisms of how NRF2 activation in HLRCC contributes to the progression of the disease are not known, and no treatments have been identified to circumvent the NRF2-mediated chemoresistance in HLRCC. This dissertation explores the roles of NRF2 in cancer, particularly HLRCC. Here, we provide a comprehensive catalog of NRF2 mutations across all tumor types, and characterize underappreciated NRF2-R34 mutations that activate the antioxidant response. We then focus on a particular cancer harboring NRF2 activation, HLRCC, and provide the first evidence of a role for NRF2 in upregulating the iron storage protein, ferritin, to induce a chronic proliferative signal in HLRCC. To circumvent the known therapeutic resistance of HLRCC, we demonstrate that HLRCC is sensitive to an iron-dependent cell death, ferroptosis. Lastly, to further characterize the NRF2 regulatory network, we systematically identify previously-unrecognized negative regulators of NRF2. This dissertation presents mechanistic insight into the iron-dependent role of NRF2 in cancer, particularly HLRCC, while simultaneously identifying new regulators for NRF2 and new treatment modalities for HLRCC. Advisors/Committee Members: Ooi, Aikseng (advisor), Chen, Qin (committeemember), Maher, Jonathan (committeemember), Wondrak, Georg (committeemember), Zhang, Donna (committeemember).

Subjects/Keywords: Cancer; ferroptosis; HLRCC; iron; NRF2; signaling

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

APA (6th Edition):

Kerins, M. J. (2019). Ironing Out Roles and Regulation of NRF2 in a Hereditary Cancer Syndrome . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/633229

Chicago Manual of Style (16th Edition):

Kerins, Michael John. “Ironing Out Roles and Regulation of NRF2 in a Hereditary Cancer Syndrome .” 2019. Doctoral Dissertation, University of Arizona. Accessed January 23, 2020. http://hdl.handle.net/10150/633229.

MLA Handbook (7th Edition):

Kerins, Michael John. “Ironing Out Roles and Regulation of NRF2 in a Hereditary Cancer Syndrome .” 2019. Web. 23 Jan 2020.

Vancouver:

Kerins MJ. Ironing Out Roles and Regulation of NRF2 in a Hereditary Cancer Syndrome . [Internet] [Doctoral dissertation]. University of Arizona; 2019. [cited 2020 Jan 23]. Available from: http://hdl.handle.net/10150/633229.

Council of Science Editors:

Kerins MJ. Ironing Out Roles and Regulation of NRF2 in a Hereditary Cancer Syndrome . [Doctoral Dissertation]. University of Arizona; 2019. Available from: http://hdl.handle.net/10150/633229

2. Li, Hui. Nonalcoholic Steatohepatitis Alters Phase I Drug Metabolism .

Degree: 2018, University of Arizona

Variable drug responses (VDRs) are dependent on inter-individual variability in the activity of drug-metabolizing enzymes. As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis (NASH) has been identified as a source of significant inter-individual variation in hepatic drug metabolism. A previous ex vivo study demonstrated significant changes in hepatic CYP activity in adult human NASH. To evaluate the current model in reflecting the hepatic CYP alterations in humans with NASH, the expression profile and the in vivo activities of multiple CYP isoforms were assessed in the prominent diabetic NASH mouse models. Although significant alterations in the profile of CYP expression and function were shown in the diabetic NASH mouse model, a comparison revealed that this model only partially recapitulates the human ex vivo CYP alteration pattern. Therefore, in vivo determination of the effects of NASH on CYP activity should be conducted in human, and more appropriate models are required for future drug metabolism studies in NASH. Compared to adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The following study determined the impact of fatty liver disease severity on the activity of a variety of CYPs in adolescents using the in vivo approach established in the first study. The CYP2C19 enzymatic activity is decreased by 60% in NASH adolescents. A comparison between the in vivo pediatric studies and a previous ex vivo study in adult indicates distinct differences in the activities of CYP1A2 and CYP2C9, which demonstrate that pediatric NASH presents an altered pattern of CYP activity and NASH should be considered as a confounder of drug metabolism for certain CYPs. Furthermore, hepatic alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play critical roles in alcohol metabolism and other cellular metabolism processes, as well as the metabolism of clinical drugs. The alterations in alcohol metabolism processes in response to human NASH progression were investigated using human liver samples. ADH and ALDH expression and function are significantly altered in the progression of NASH, which may have a notable impact on ADH and ALDH associated cellular metabolism processes and lead to significant alterations in drug metabolism mediated by these enzymes. Overall, the major phase I drug metabolizing enzymes are profoundly altered in the progression of human NASH, which may significantly increase the incidence of VDRs. Therefore, the disease state of NASH should be taken into consideration in dosage recommendations and appropriate dose adjustment. Future studies will be needed to translate these findings to guide actual clinical practice. Advisors/Committee Members: Cherrington, Nathan J (advisor), Zhang, Donna (committeemember), Klimecki, Walter T. (committeemember), Wright, Stephen H. (committeemember), Maher, Jonathan M. (committeemember).

Subjects/Keywords: Adverse Drug Reactions; Alcohol Metabolism; Cytochrome p450; Nonalcoholic Steatohepatitis; Phase I Metabolism

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

APA (6th Edition):

Li, H. (2018). Nonalcoholic Steatohepatitis Alters Phase I Drug Metabolism . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/627774

Chicago Manual of Style (16th Edition):

Li, Hui. “Nonalcoholic Steatohepatitis Alters Phase I Drug Metabolism .” 2018. Doctoral Dissertation, University of Arizona. Accessed January 23, 2020. http://hdl.handle.net/10150/627774.

MLA Handbook (7th Edition):

Li, Hui. “Nonalcoholic Steatohepatitis Alters Phase I Drug Metabolism .” 2018. Web. 23 Jan 2020.

Vancouver:

Li H. Nonalcoholic Steatohepatitis Alters Phase I Drug Metabolism . [Internet] [Doctoral dissertation]. University of Arizona; 2018. [cited 2020 Jan 23]. Available from: http://hdl.handle.net/10150/627774.

Council of Science Editors:

Li H. Nonalcoholic Steatohepatitis Alters Phase I Drug Metabolism . [Doctoral Dissertation]. University of Arizona; 2018. Available from: http://hdl.handle.net/10150/627774

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