Browsing by Subject "AR"
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Item Application of targeting nucleases to modeling prostate cancer gene rearrangements(2014-06) Nyquist, Michael D.Advanced prostate cancer (PCa) treated with androgen deprivation therapy (ADT) eventually relapses to an ADT-resistant disease referred to as castration resistant PCa (CRPC). Recent integrative analyses of PCa genomes have led to the elucidation of potential subtypes that are revelatory to the development of PCa as well as the mechanisms of resistance to ADT and CRPC progression. These studies have confirmed that alterations in the androgen receptor (AR) signaling axis are central to CRPC progression, and have uncovered complex mechanisms by which AR and other components of the AR signaling axis affect, and are affected by, genomic changes and epigenetic transformations. Among the most frequent alterations in CRPC are direct alterations in the AR gene. These AR gene alterations include AR amplification, point mutations, and more recently AR gene rearrangements leading to expression of truncated, constitutively active AR splice variants that are impervious to ADT. Fortunately, the recent development of transcription activator-like effector nucleases (TALENs) has allowed researchers to tailor the genomes of their model systems more rigorously than ever before. This dissertation presents studies centered on genome engineered cell lines modeling intragenic-AR rearrangements that are associated with the production of androgen receptor splice variants. In the second chapter, two AR rearrangements associated with ARv567es expression were recreated in PCa cell line R1-AD1 using targeting nucleases. These engineered cell lines expressed high levels of Arv567es that recapitulated the full length AR transcriptome and drove androgen independent growth. In chapter three, AR rearrangements associated with high AR-V7 expression in CRPC cell lines CWR-R1 and 22Rv1 were induced and gene-corrected, respectively, using targeting nucleases. We found that a deletion contained in AR intron 1 of CWR-R1 was not sufficient to induce AR-V7 expression. However, genetic correction of a duplicated AR intron 3 region found in 22Rv1 decreased AR-V7 levels. These models were developed to determine the underlying mechanisms of AR variant production as well as provide a novel platform with which to study AR variant DNA binding, transcriptional regulation, and clinically relevant aspects of PCa such as biomarker research and precision medicine.Item Exploring Student Engagement in an Augmented Reality Game(2017-06) VanMeerten, NicolaasIt has been argued that approaches to education should embed learning in activities that reflect the social and physical environments in which the knowledge is relevant. Only recently, did it become possible to situate learning in a variety of novel contexts using augmented reality (AR) games. This study investigates the behaviors of middle school students during their participation in an AR game called Play the Past. The findings of this study show that engagement differed during discrete activities in the game environment and that there was a relationship between the roles that students were assigned and their engagement.