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Proteomic Analysis Reveals Fkbp51 And Fkbp52 Interactors Implicated In Androgen Receptor-Mediated Castration Resistant Prostate Cancer, Olga Soto

Open Access Theses & Dissertations

Aberrant signaling mechanisms by the Androgen Receptor (AR) are attributed as the main culprits for the initiation and progression of prostate cancer (PCa). Due to its dependence on androgens, research efforts have focused on developing strategies to directly target androgen-mediated receptor activity. However, given the recurrence and treatment resistance of PCa despite androgen targeted therapies, recent efforts have shifted to find novel targets against the disease. These efforts include further revealing the molecular components and their mechanisms underlying AR signaling in both normal and disease physiological settings. Hence, our lab's work is focused on characterizing and targeting molecular chaperones that …

A Genomic Approach To Assessing The Fkbp52-Regulated Androgen Receptor Cistrome And Transcriptome, Nina Raquelle Ortiz

Open Access Theses & Dissertations

Androgen receptor (AR)-regulated genes contribute to the initiation and progression of prostate cancer. Receptor signaling persists and plays a pivotal role in late-stages of the disease, for which there is currently no treatment. Thus, there is a need to understand the mechanisms regulating AR function as a means to identify drug targets for potential therapeutics. The FKBP52 cochaperone has emerged in recent years as a regulator of AR activity that is functionally linked in the AR signaling pathway. FKBP52 is a known positive regulator of AR and believed to interact with AR at its binding function 3 surface (BF3), a …

Computational Molecular Docking Models And Design Of Diarylpentanoids For The Androgen Receptor, Jarett Guillow

Computational and Data Sciences (MS) Theses

The androgen receptor (AR) is a member of the nuclear receptor protein family that, upon binding to its natural ligand dihydrotestosterone (DHT) in the cytoplasm, translocates to the nucleus and exerts nuclear transcription factor activity to drive gene expression related to normal prostate development. AR signaling becomes overactive during the development and progression of prostate cancer through different mechanisms, including over-expression and mutation of the AR. Therefore, the AR is a prominent molecular target in the clinical management of prostate cancer. However, all therapeutic modalities targeting the AR, including androgen ablation therapy and AR block suffer from transient efficacy and …

Prostate Cancer Resistance To Cabazitaxel Chemotherapy, Diane Begemann

Theses and Dissertations--Toxicology and Cancer Biology

The plasticity of prostate tumors contributes to the heterogeneity in response and acquisition of therapeutic resistance in advanced prostate cancer. Disruption of the phenotypic landscape via epithelial-mesenchymal transition (EMT) enables prostate tumors to invade and metastasize. Our previous studies demonstrated that cabazitaxel (a 2^nd generation FDA-approved taxane chemotherapy) that is used for treatment of castration-resistant prostate cancer (CRPC), causes reversal of EMT to mesenchymal-epithelial transition (MET). The present study examined the effect of sequencing cabazitaxel chemotherapy mediated MET on prostate tumor re-differentiation and its impact on overcoming resistance in models of advanced prostate cancer.

The presence of DHT (1nM) …

Sex Differences In Uropathogenic Escherichia Coli Urinary Tract Infection, Patrick David Olson

Arts & Sciences Electronic Theses and Dissertations

Urinary tract infections (UTIs) are among the most common bacterial infections which plague humans. Community-onset UTI is widely viewed as a disease only of women; indeed, its occurrence between 2 and 60 years of age is almost exclusive to females. However, the disease also affects substantial male patient populations, namely infants and the very elderly. While female cases of complicated and upper-tract UTI (pyelonephritis) outnumber male cases overall, men carry an increased risk of mortality from these infections. Sex differences in UTI epidemiology have heretofore been attributed almost entirely to anatomic and hygienic factors in females, including the permissiveness of …

Identification And Characterization Of Small Molecules Targeting Fkbp52 As A Novel Treatment For Prostate Cancer, Naihsuan C. Guy

Open Access Theses & Dissertations

Prostate cancer (PCa) is one of the most commonly diagnosed diseases and the second leading cause of cancer deaths among men worldwide. Its growth is dependent upon androgen receptor (AR) signaling and the mainstay for treatment is hormone-ablation therapy using antiandrogens and/or androgen-deprivation therapies (ADT). Treatment of PCa with antiandrogens and/or ADT are initially effective; they act to repress the AR by directly competing with androgens for the ligand binding domain (LBD) and prevent activation of the receptor resulting in tumor regression. Unfortunately, the resistance to these treatments invariably emerges and results in a much more aggressive form of tumor …

Development Of A Yeast-Based Assay For The Functional Characterization Of Fkbp52/ Î?-Catenin Interactions With The Androgen Receptor, Theresa Anne Rodriguez

Open Access Theses & Dissertations

Prostate cancer development is uniquely dependent on the androgen receptorâ??s (ARâ??s) transcriptional regulation in response to hormone binding. Current therapies directly target AR acting as an antagonist at androgen binding sites. However, once androgen-dependence is lost, meaning the patient has progressed into a late-stage hormone resistant phenotype, all current treatments are essentially ineffective. Utilizing the yeast strain Saccharomyces cerevisiae we are capable of creating a model system that allows for the exogenous expression of AR while still retaining the chaperone components needed for this steroid receptor complex. The 52kDa FK506 binding protein (FKBP52) has been shown to be an important …

A Novel Fkbp52/Β-Catenin Complex Specifically Regulates Androgen Receptor Activity, Cheryl Lynne Storer

Open Access Theses & Dissertations

The androgen receptor complex plays an essential role in prostate cancer progression due to exploitation of the androgen receptor (AR) as a transcription factor. The final stage of the receptor complex consists of a dimerized receptor, a dimeric heat shock protein (Hsp90), the cochaperone p23, and an immunophilin. Hormone-dependent prostate cancer progresses due to key interactions between the androgen receptor complex and its ligand α dihydrotestosterone (DHT). While current treatments focus on blocking the androgen receptor-ligand interactions, these therapies are no longer effective in advanced stage, hormone-refractory prostate cancer (HRPC).

Therefore, we have been interested in targeting other members of …

Identification And Characterization Of Fkbp52-Specific Inhibitors For The Treatment Of Prostate Cancer, Johanny Tonos De Leon

Open Access Theses & Dissertations

Steroid hormone receptors require the ordered assembly of various chaperone and cochaperone proteins in order to reach a functional state. The final stage in the receptor maturation process requires the formation of a mutimeric complex consisting of Hsp90 dimer, p23, and one of several large immunophilins. Studies conducted previously demonstrated that the large immunophilin FKBP52 acts to potentiate glucocorticoid, androgen, and progesterone receptor signaling pathways. The aim of these studies was to identify and characterize FKBP52-specific inhibitors that would not only serve as tools for the pharmacological analysis of FKBP52-receptor interactions, but may also lead to novel drugs with significant …

The Role Of Androstane Neurosteroids In Alcohol-Mediated Social Behavior, Jason J. Paris

Legacy Theses & Dissertations (2009 - 2024)

Androgenic steroids, such as testosterone, may influence the propensity for aggression in both people and animals. Some of testosterone's effects on aggression may be due, in part, to its metabolic products that are 5á-reduced and 3á-hydroxylated to form, 3á-androstanediol (3á-diol), which can also enhance aggression in mice. Notably, alcohol (EtOH) consumption facilitates aggression in people and animals, particularly among those predisposed to act aggressively. In rats, EtOH can increase 3á-diol in prefrontal cortex, which may facilitate aggression. The present work aimed to elucidate the role of 3á-diol for EtOH-enhanced aggression. We hypothesized that EtOH would enhance inter-male aggression, social dominance, …

Relationship Between Cag Repeats Of The N Terminal Region Of The Androgen Receptor And Body Shape, Michael John Wen

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

Androgen receptor (AR) gene CAG polymorphisms may be associated with body shape, and are associated with certain breast and prostate cancers. In addition, body shape is associated with risk for a variety of diseases, including heart disease, diabetes, and certain forms of cancer. The CAG repeat in exon l of the AR gene was quantified using Perkin Elmer Applied Biosystems GeneScan analysis software in 96 and 59 healthy Caucasian men and women, respectively, who were over the age of 50 years. All participants had body measurements taken and donated a blood sample. Waist measurements included circumferences at the 1) umbilicus …