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dc.contributor.authorKhan, Zainab
dc.date.accessioned2021-05-12T19:04:18Z
dc.date.available2021-05-12T19:04:18Z
dc.date.issued2021
dc.identifier.urihttp://hdl.handle.net/10150/658264
dc.descriptionA Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.
dc.description.abstractAlzheimer’s disease (AD) is the most common form of dementia affecting millions of people; however, treatment options are currently limited. Previous studies have shown potential to slow the progression of AD by 4-[1-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)- ethenyl]benzoic acid (bexarotene), an antineoplastic agent modeled after a vitamin A derivative, in animal models. Bexarotene binds to the retinoid X receptors (RXRs) and stimulates RXR homodimerization and activation of RXR target genes. It also impacts RXR heterodimerization with other nuclear receptors, including the liver-X-receptor (LXR) and retinoic acid receptor (RAR). Bexarotene’s reversal of beta amyloid (Aβ) plaques in mouse models likely occurs via RXR-LXR activation and induction of apolipoprotein E (ApoE) expression. However, bexarotene has many adverse effects, including hyperlipidemia, skin toxicity, hypothyroidism, etc. The current study developed and tested novel bexarotene analogues for their ability to upregulate ApoE expression, crucial in AD neuroprotection, without producing the significant adverse effects of hyperlipidemia and skin toxicity through upregulation of sterol regulatory element-binding protein (SREBP) and activation of RAR, respectively. In order to test bexarotene analogues, luciferase assays were performed in both human colon cancer and human embryonic kidney cell lines. Two screening assays were completed to assess their ability (1) to induce RXR homodimerization through mammalian two-hybrid assays (M2H) and (2) to induce RXR responsive element DNA sequence (RXRE) based transcription. We then assessed the ability of the analogues (1) to induce ApoE expression through LXRE-based luciferase assays, while evaluating their potential for adverse effects through (2) SREBP- and (3) RARE-based reporter systems. Results from the M2H and RXRE assays revealed that our novel analogues produce a wide range of transcriptional activity. LXRE, SREBP, and RARE assays revealed similar results. Specifically, analogue A44 had significantly higher activity with LXRE (p < 0.05) and significantly lower activation via SREBP (p < 0.05) and RARE (p < 0.05) as compared to bexarotene. These assays revealed that our novel bexarotene analogues can potentially be more effective and potent RXR ligands than bexarotene with the capability to circumvent RAR cross-over and elevated SREBP expression, and thus the adverse effects of bexarotene. These analogues may have the potential to slow the progression of AD through increased ApoE expression without the current limitations associated with bexarotene use.en_US
dc.language.isoen
dc.publisherThe University of Arizona.
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the College of Medicine - Phoenix, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectAlzheimer's diseaseen_US
dc.subjectbexaroteneen_US
dc.subjectretinoid X receptoren_US
dc.subjectRXRen_US
dc.titleBiological evaluation of potential retinoid X receptor-selective agonists: the search for a more effective treatment for Alzheimer’s diseaseen_US
dc.typeThesis
dc.typePoster
dc.typetext
dc.contributor.departmentThe University of Arizona College of Medicine - Phoenix
dc.description.collectioninformationThis item is part of the College of Medicine - Phoenix Scholarly Projects 2021 collection. For more information, contact the Phoenix Biomedical Campus Library at pbc-library@email.arizona.edu.
dc.contributor.mentorJurutka, Peter
refterms.dateFOA2021-05-12T19:04:19Z


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