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Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective

Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.
ContributorsYang, Joanna (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Hibler, Elizabeth (Committee member) / Barrett, The Honors College (Contributor)
Created2012-05
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Description
Psoriasis is a skin disease that affects millions of individuals. Genetic risk factors for psoriasis include a common deletion of two late cornified envelope (LCE) genes (LCE3B and LCE3C) located within a cluster of genes expressed during epithelial differentiation and skin repair. It was previously discovered that treatment with 1,25-dihydroxyvitamin

Psoriasis is a skin disease that affects millions of individuals. Genetic risk factors for psoriasis include a common deletion of two late cornified envelope (LCE) genes (LCE3B and LCE3C) located within a cluster of genes expressed during epithelial differentiation and skin repair. It was previously discovered that treatment with 1,25-dihydroxyvitamin D3 (1,25D) or analogs thereof can improve psoriasis symptoms in many patients, but the molecular mechanisms for this action are largely unknown. Our laboratory previously showed that 1,25D as well as low affinity ligands for the vitamin D receptor (VDR), such as delphinidin and cyanidin, are capable of upregulating the remaining LCE3A, -3D, and -3E genes to potentially compensate for the loss of LCE3B and -3C in promoting skin repair. In the current study, DHA and curcumin were tested and found to also upregulate LCE3 transcripts in a dose-dependent manner. To investigate other potential target genes for 1,25D and DHA, we tested JunB, for which low or absent expression has been reported to cause or be associated with psoriatic lesions. Our experiments showed a trend for an upregulation of JunB mRNA after DHA treatment, potentially providing benefit for psoriasis patients. Although our hypothesis is that DHA functions as a vitamin D receptor ligand to mediate upregulation of JunB and LCE3 genes, other investigators have assumed that DHA actions in skin are mediated via PPAR isoforms. We therefore utilized a selective ligand for PPAR delta (GW501516) to determine whether PPAR delta, the primary PPAR isoform in keratinocytes, is a mediator of DHA-induced LCE3 gene activation. Although a modest upregulation of LCE3 genes was seen after treatment with GW501516, our findings are still consistent with DHA acting primarily as a VDR ligand. Our results not only provide additional information about the ability of VDR ligands to upregulate specific skin genes with relevance for skin repair, but also may help provide a molecular basis for testing improved treatments for mild to moderate psoriasis.
ContributorsKarrys, Amitis (Author) / Jurutka, Peter (Thesis director) / Whitfield, Kerr (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05