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Dhhc5 Regulates Beta-Adrenergic Signaling In The Heart Through Palmitoylation Of G Alpha Proteins, Jie Chen

Dissertations and Theses (Open Access)

S-palmitoylation is a reversible posttranslational modification that plays an important role in regulating protein localization, trafficking, and stability. Recent studies have shown that some proteins undergo extremely rapid palmitoylation/depalmitoylation cycles after cellular stimulation supporting a direct signaling role for this posttranslational modification. The work in this dissertation investigated whether β-adrenergic stimulation led to stimulus-dependent palmitoylation of downstream signaling proteins in immortalized and primary cell models. I found that β-adrenergic stimulation led to rapidly increased Gαs and Gαi palmitoylation only in primary cardiomyocytes. The kinetics of palmitoylation was temporally consistent with the downstream production of cAMP and contractile responses. I identified …

Obscurin Mediates Ankyrin Complex Formation In The Heart, Janani Subramaniam

Dissertations and Theses (Open Access)

Distinctly organized domains of receptors, ion channels, transporters, signaling molecules, cell adhesion molecules, and contractile proteins are crucial to cardiac function. Interactions between adaptor proteins such as ankyrins and cytoskeletal proteins such as obscurin play a pivotal role in organizing these functional domains in cardiomyocytes. Therefore, dysfunction of both ankyrin as well as obscurin lead to a host of cardiovascular diseases such as arrhythmias and cardiomyopathies. Alternative splicing of ankyrin yields numerous isoforms that interact with obscurin at various sub-cellular domains. And while some of these obscurin-ankyrin complexes have been studied, many others have not been characterized. Further, previous studies …

Tracking Treatment Response And Resistance To Parp Inhibition (Talazoparib) In Hereditary Pancreatic Cancer., Jennifer Goldstein

Dissertations and Theses (Open Access)

polyADP ribose polymerase (PARP) inhibitors are a class of drugs that block the PARP enzymes, involved in the repair of singe-stranded DNA breaks through the base excision repair pathway. PARP inhibition leads to replication-associated double stranded DNA breaks, which are repaired by homologous recombination (HR). In tumors with HR defects (i.e. BRCA mutants), there is a shift to error-prone DNA repair and subsequent genomic instability and cell death.

In 2014, Olaparib became the first FDA-approved PARP inhibitor for the treatment of BRCA-mutant ovarian cancer. In the phase III POLO (Pancreas cancer OLaparib Ongoing) trial presented at the American Society …

Bilirubin Nanoparticle As An Anti-Inflammatory Therapy For Graft Versus Host Disease, Sumedha Pareek

Dissertations and Theses (Open Access)

Graft versus host disease (GvHD) caused by alloreactive donor lymphocytes is a fatal complication of hematopoietic stem cell transplant (HSCT). Myeloablative conditioning regimen, consisting of chemotherapy and/or radiation, given prior to HSCT can cause tissue damage. This non-specific tissue damage triggers cross-presentation of alloantigens to the donor immune cells, causing recruitment of leukocytes and production of inflammatory cytokines. Targeting this inflammation without affecting the anti-leukemia effects of HSCT, continues to be one of the biggest challenge in finding a therapy for GvHD. Bilirubin is a tetrapyrrole pigment, found in the blood, with natural anti-oxidative and anti-inflammatory properties. Using mouse models …

Role Of Nudt21 Mediated Alternative Polyadenylation And Hyaluronan In The Development Of Pulmonary Hypertension, Scott Dale Collum

Dissertations and Theses (Open Access)

Pulmonary hypertension (PH) is a progressive disease with serious effects on quality of life and life expectancy of patients. PH is a complex disease that likely develops due to multiple influences, and no curative treatments exist for this disease. It has been shown that alternative polyadenylation (APA) due to depletion of Nudix Hydrolase 21(NUDT21) is involved in several disease states including the chronic lung disease idiopathic pulmonary fibrosis (IPF). Additionally, hyaluronan, an extracellular matrix glycosaminoglycan has been associated with PH. The role and mechanism of NUDT21 and hyaluronan have not yet been described in this disease. My results reveal that …

Investigations Of The Structure-Function Relationship In Kainate Receptors Using FöRster Resonance Energy Transfer, Douglas Litwin

Dissertations and Theses (Open Access)

Kainate receptors belong to the family of ion channels known as the ionotropic glutamate receptors. Ionotropic glutamate receptors mediate the majority of excitatory synaptic transmission, modulate the release of presynaptic glutamate, and facilitate dendrite formation. Kainate receptors are unique among the ionotropic glutamate receptors in being modulated by sodium ions. They have also been implicated in the development of higher learning and epilepsy. In recent years a wealth of structural data has become available for the AMPA and NMDA classes; however, the structural characterization of kainate receptors has been limited. The work in this dissertation utilizes luminescence resonance energy transfer …

Modeling Cancer Using Li-Fraumeni Syndrome Patient-Derived Induced Pluripotent Stem Cells, Ruoji Zhou

Dissertations and Theses (Open Access)

Li-Fraumeni syndrome (LFS) is an autosomal dominant disease caused by germline mutations in the gene TP53, which predispose individuals to a wide range of malignancies, including osteosarcoma and breast cancer. In the previous study, our group developed a novel disease model platform by reprograming LFS patients' fibroblasts to induced pluripotent stem cells (iPSCs), and further differentiate these iPSCs into mesenchymal stem cells (MSCs) then to osteoblasts (OBs), the cells from which osteosarcomas originate. Interestingly, LFS iPSC-derived osteoblasts recapitulated the osteosarcoma phenotype, creating “a bone tumor in a dish”. This “tumor in a dish” platform proved that LFS is an …

Deubiquitinating Enzymes Promote Cancer Progression And Metastasis Via Regulating Protein Stability, Zhenna Xiao

Dissertations and Theses (Open Access)

Deubiquitinating enzymes (DUBs, also called deubiquitinases) are enzymes that remove monoubiquitin or polyubiquitin chains from target proteins. DUBs have critical roles in cell homeostasis and signal transduction, as they regulate protein degradation, subcellular localization, and protein-protein interaction. Deregulation of DUBs contributes substantially to tumor formation and progression, and therefore targeting DUBs may be a promising cancer therapy strategy. My dissertation focuses on identifying the DUBs of EZH2 and SNAI1, two proteins critical for cancer progression and metastasis, and establishing these DUBs as promising anti-cancer targets.

EZH2, the catalytic component of the PRC2 complex, silences gene transcription by histone methylation. High …

Quantifying Uncertainty In A Measurement-Based Assessment Of Relative Biological Effectiveness In Carbon Ion Radiotherapy, Shannon Hartzell

Dissertations and Theses (Open Access)

One of the largest inconsistencies in dose delivered during carbon ion therapy is due to uncertainties in relative biological effectiveness (RBE), a value that is calculated via one of several clinically implemented algorithms. This study investigates the uncertainty in measured microdosimetric parameters for RBE calculation by the Microdosimetric Kinetic Model (MKM), Repair Misrepair Fixation model (RMF), and Local Effect Model I (LEM) using a Tissue Equivalent Proportional Counter (TEPC).

Microdosimetric spectra, kinetic energy spectra, and dose fragment contributions were calculated using Monte Carlo (GEANT IV) for monoenergetic and SOBP carbon beams of clinical energy. From microdosimetric spectra, lineal energy values …

Dissecting The Roles Of Human Smc Complexes In Transcription Regulation And Chromatin Organization, Ruoyu Wang

Dissertations and Theses (Open Access)

Metazoans utilize a constellation of distal regulatory elements to control gene transcription, and therefore they have to forge highly complex chromatin loops to spatially bridge these regulatory elements and genes in the three-dimensional (3D) genome. However, the hierarchy of chromatin contacts and their underlying mechanisms are not well-understood. SMC complexes including Cohesin complex and Condensin complex has been widely proposed to organize 3D genome structure, and further regulate metazoans’ gene transcription. Here, we aim to dissect the direct functions of SMC complexes (both Cohesin and Condensin) in transcriptional regulation and 3D genome organization, by utilizing an inducible protein degradation system. …

P53r245w Mutation Elicits Metastatic Phenotype In Pten Deficient Prostate Cancer, Ky Pham

Dissertations and Theses (Open Access)

Trp53 mutations are the most frequent genetic alterations in prostate cancer and are associated with more aggressive disease and worse overall survival. The majority of Trp53 mutations in prostate cancer are missense mutations, resulting in amino acid substitutions with profound effect. In addition to the loss of wild type function, missense mutations in Trp53 result in a gain-of-function (GOF) phenotype. This GOF phenotype confers biologic advantages to the tumor cells, enabling them to metastasize and invade distant organs. In this study, we generated mice carrying a conditional prostate-specific p53R245W mutant and Pten deletion to access the role of this common …

Fasting Reduces Intestinal Radiotoxicity Enabling Dose-Escalated Radiotherapy For Pancreatic Cancer, Marimar De La Cruz Bonilla

Dissertations and Theses (Open Access)

Surgical resection is the only potentially curative treatment for pancreatic cancer, but only 15-20% of patients have resectable tumors. In unresectable cases, stereotactic body radiotherapy (SBRT) may be used to give tumor-directed radiotherapy (RT). Unfortunately, this can cause severe gastrointestinal (GI) toxicity due to proximity of the pancreatic head to the duodenum. Protecting the intestine from the toxic side-effects of radiation may enable dose-escalation that could achieve more effective local control of disease. We and others have previously shown that a fast of 24 hours protects mice from lethal doses of the DNA-damaging agent etoposide. In this study, we demonstrate …

Investigating The Role Of Cd109 In Pancreatic Ductal Adenocarcinoma, Mennatallah Shaheen

Dissertations and Theses (Open Access)

Pancreatic Ductal Adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the US. We performed loss of function genomic screening on a cohort of four patient derived PDAC cell populations and our data shows a cell surface receptor CD109 to be a common vulnerability, the biologic role of which in PDAC is yet unstudied and largely unknown. We hypothesized that CD109 expression provides PDAC cells with a survival advantage, and promotes cancer progression through activation of downstream signaling. We believe therefore that targeting CD109 could improve PDAC patients’ survival. Here we report that CD109 plays a role in …

Gcn5 Loss Impacts Myc-Driven Cancer In Mice And Human Cells, Aimee Farria

Dissertations and Theses (Open Access)

GCN5 is the catalytic subunit in the acetyltransferase module of SAGA and ATAC, multiprotein complexes involved in the modification of histone and nonhistone proteins. GCN5 is most recognized as a co-activator of gene transcription. The SAGA complex is recruited to chromatin by transcription factors such as MYC and E2F1 where GCN5 acetylates H3K9 leading to a more open and accessible chromatin structure. Previous research has demonstrated that GCN5 also acetylates MYC, a protein that amplifies the expression of cancer-promoting genes and is frequently dysregulated in cancer, increasing its stability. Our lab has found there is a significant overlap in the …

Molecular Consequences Of High Taz Expression In Gliomas, Visweswaran Ravikumar

Dissertations and Theses (Open Access)

Diffuse high grade gliomas are complex and lethal neoplasms of the adult central nervous system that are driven by a range of genetic and epigenetic alterations. Molecular classification of these tumors has identified different transcriptional subtypes, the most notable being Proneural (PN) and Mesenchymal (MES) classes. The most aggressive forms of the disease have a Mesenchymal expression signature, with reported PN-to-MES transition occurring with tumor progression. Master regulatory analysis has identified the transcriptional co-activator TAZ (WWTR1) as a major driver of the MES transition. Overexpression of this single protein in glioma stem cells has been shown to drive a transition …

Microrna-374a, -4680, And -133b Suppress Cell Proliferation Through The Regulation Of Genes Associated With Human Cleft Palate In Cultured Human Palate Cells, Akiko Suzuki, Aimin Li, Mona Gajera, Nada Abdallah, Musi Zhang, Zhongming Zhao, Junichi Iwata

Faculty, Staff and Student Publications

BACKGROUND: Cleft palate (CP) is the second most common congenital birth defect; however, the relationship between CP-associated genes and epigenetic regulation remains largely unknown. In this study, we investigated the contribution of microRNAs (miRNAs) to cell proliferation and regulation of genes involved in CP development.

METHODS: In order to identify all genes for which mutations or association/linkage have been found in individuals with CP, we conducted a systematic literature search, followed by bioinformatics analyses for these genes. We validated the bioinformatics results experimentally by conducting cell proliferation assays and miRNA-gene regulatory analyses in cultured human palatal mesenchymal cells treated with …

The Influence Of Vitamin D Supplementation On Local And Systemic Inflammatory Markers In Periodontitis Patients: A Pilot Study, Mohamed M Meghil, Lance Hutchens, Anas Raed, Neha A Multani, Mythilypriya Rajendran, Haidong Zhu, Stephen Looney, Mahmoud Elashiry, Roger M Arce, Mark E Peacock, Yanbin Dong, Christopher W Cutler

Faculty, Staff and Student Publications

OBJECTIVES: Vitamin D deficiency/insufficiency is a worldwide public health issue that has been linked to numerous inflammatory disorders, including periodontitis. There is increasing support for a role for adequate vitamin D levels in overall health. Populations with darker skin color have a higher prevalence of vitamin D deficiency/insufficiency and periodontitis. The purpose of this small pilot study was to investigate the influence of 12 weeks of 25(OH)D vitamin D supplementation (VDS) on mediators of systemic inflammation in dark-skinned, periodontitis patients.

MATERIALS AND METHODS: A total of 23 patients with moderate to severe periodontitis were randomly assigned to the vitamin D …

Autonomic Response In Autism Spectrum Disorder: Relationship To Social And Cognitive Functioning, Michelle A Patriquin, Elizabeth M Hartwig, Bruce H Friedman, Stephen W Porges, Angela Scarpa

Staff and Researcher Publications

Individuals with autism spectrum disorder (ASD) may exhibit chronic autonomic nervous system (ANS) hyperarousal (e.g., lower respiratory sinus arrhythmia and higher heart rate) compared to their typically developing peers, reflecting a chronic biological threat response. The sustained nature of this cardiac threat suggests tonic nervous system perception of threat in safe contexts. Herein, the cardiac literature in adult and child populations with ASD is reviewed and placed within a continuum of functioning in order to inform the relationship between cardiac response and functioning in ASD. Findings from this review support the relationship between chronic autonomic hyperarousal and emotional and behavioral …

An Examination Of Student Performance In Pre-Requisite Coursework And Upper Division Nursing Coursework, Jennifer L. Brown, Cheryl M. Smith

Journal of Nursing & Interprofessional Leadership in Quality & Safety

Admission and retention of qualified nursing students are essential in meeting the demands of a rapidly changing health care environment and nursing shortage. The purpose of this exploratory correlational study was to determine the relationship between student performance in quantitative pre-requisite coursework and student performance in upper division nursing coursework in order to identify students at-risk for attrition. A series of descriptive and correlational analyses were conducted using pre-existing institutional data. A moderate relationship existed among the chemistry II and first-year upper division nursing courses (r = .21 to r = .40). These results suggest that prerequisite chemistry course …

The Man With 2 Hearts: 25 Years From Heterotopic To Orthotopic Heart Transplantation, Elizabeth L Godfrey, Michael L Kueht, Abbas Rana, O H Frazier

The Texas Heart Institute Journal

Substantial technological advances in mechanical circulatory support have caused a shift in the management of end-stage heart failure. From the 1970s through the 1990s, heterotopic heart transplantation was routinely performed in patients in whom orthotopic transplantation was likely to fail. Heterotopic heart transplantation is now performed less often because modern mechanical circulatory assist devices are routinely used as bridges to orthotopic transplantation; regardless, the operation has helped numerous patients who would not otherwise have received adequate allografts. We describe the case of a man with idiopathic nonischemic cardiomyopathy who, at age 17, was given an ABO- and size-matched heterotopic allograft …

The Effect Of Meditation On Stroke-Survivor Resilience: Secondary Analysis Of Existing Data, Mary Love

Dissertations and Theses (Open Access)

Purpose: To test the effect of meditation on resilience of community-dwelling stroke survivors, and to identify resilience predictor variables in these survivors.

Methods: Sub-study with secondary analysis of existing data from the parent study, MEditatioN for post stroke Depression (MEND). Paired samples t-test was used to evaluate the effect of meditation on resilience of stroke-survivors (n=20) in the intervention group. Bivariate analysis and general linear modeling (GLM) were used to identify demographic, clinical, and psychological predictor variables of baseline resilience for all stroke survivors (n=34).

Results: The increase in stroke-survivor resilience scores from baseline (mean 3.46, SD=.81) to intervention completion …

Exploring Prenatal Risk Factors Among Hispanic Children With Autism Spectrum Disorders. – A Pilot Study In The Rio Grande Valley, Lauren Tien

Dissertations and Theses (Open Access)

Background: Peer-reviewed studies suggest that a hostile gestational environment is associated with delayed neurological development in infants. Autism spectrum disorder (ASD) is estimated to affect 1 in 59 children in the United States; however, few studies have specifically investigated risk factors for autism in Hispanic children. Purpose: The University of Texas RGV Hispanic Autism Research Center (HARC) studied Hispanic children with ASD and their biological mothers to identify potential environmental exposures and prenatal risk factors that could impact the risk for ASD through preliminary research in the Rio Grande Valley. Methods: This pilot study recruited 25 Hispanic mothers and their …

The Prevalence Of Practicing Safety Professionals’ Knowledge, Involvement, And Competency Associated With Workplace Wellness Programs: Gauging The Safety Profession’S Engagement With The Total Worker Health Initiative, Jennifer C. Laine

Dissertations and Theses (Open Access)

The morbidity and mortality burden of occupational injuries and illnesses in the United States became such a public health concern that in 1970 the Occupational Safety and Health Act was signed into law. This law requires employers to provide workplaces “free from recognized hazards” and spurred the development of specific regulations along with the creation of academic and professional training programs to educate individuals about the safety sciences and careers in safety fields. Today there are an estimated 26,000 professionally trained and board certified safety professionals supporting workplace programs across the country, alongside numerous non-certified, but degreed, practicing safety professionals. …

Predictors Of On-Treatment Mortality Of Patients Undergoing Palliative Radiation Therapy: Improving The Quality Of End-Oflife Cancer Care, Matthew Stephen Ning

Dissertations and Theses (Open Access)

PURPOSE: Excessive medical treatment at end-of-life is an indicator of poor quality care. While radiation therapy (RT) is effective for palliation, some patients die shortly after or even during treatment. Any treatment that requires terminal patients to spend significant time in the hospital setting contradicts palliative goals. This study investigates patterns of end-of-life RT to inform quality improvement initiatives.

METHODS: All patients who died within 6 months of starting RT at a single large academic cancer center between 2015 through 2018 were identified through our institutional databases on an Institutional Review Board-approved protocol. Clinical factors including age, treatment service, number …

Impact Of Adult Attachment Style On Outcome Trajectories In A Parent-Focused Early Language Development Intervention, Cary Cain

Dissertations and Theses (Open Access)

Background: Disparities in early language development have been noted for children from low-income homes, which can impact their educational and health trajectory. The quantity and quality of language exposure in the home environment influences a child’s language development. Adult attachment style is a predictor of parenting behavior and could impact critical interactions between the parent and child. Evidence demonstrates that differences in adult attachment style impact program participation and outcomes in early childhood parenting programs delivered through home visitation.

Aims: The aims of this study were to 1) explore the association of adult attachment style on intervention outcome trajectories from …

Relationships Among Optimism, Inflammation, And Stroke Recovery, Yun-Ju Lai

Dissertations and Theses (Open Access)

Objective: Post-stroke inflammation is detrimental to the brain and results in an unfavorable recovery. Optimism has been associated with lower inflammation and better health outcomes among people with medical conditions, but no studies have assessed this association in the stroke population. The overall goals were to examine the relationships among optimism, stroke severity, physical disability, and inflammation during hospitalization and evaluate the relationships among optimism, inflammation, and stroke recovery over the three-month post-stroke period.

Methods: This study was a secondary analysis of data collected from the BioRepository of Neurological Diseases biobank. Outcomes included optimism, stroke severity, physical recovery, and inflammatory …

Waiting For A Liver Transplant: A Qualitative Study, Ayoka Badmus

Dissertations and Theses (Open Access)

Background: Advances in liver transplantation have significantly improved survival rates, making liver transplant a viable option for those with End Stage Liver Failure (ESLF). However, patients diagnosed with ESLF may experience a significant period of waiting before a liver transplant surgery, due to a limited supply of donor livers. Empirical evidence is scarce on the experience of patients waiting for a liver transplantation.

Objective: The objective of this study was to explore the waiting experience of patients diagnosed with ESLF and to identify their perceived challenges and needs while waiting for a liver transplant.

Methods: Using a generic qualitative …

Assessing The Impact Of Environmental Factors On Sedentary Behavior, Brandy Baker

Dissertations and Theses (Open Access)

Objectives Mexican Americans are burdened with many of the same noncommunicable diseases present in sedentary populations. Those living on the Texas/Mexico border have higher rates of obesity and diabetes than others in the nation. Sedentary behavior and perceptions of the environment have not been well studied among Mexican Americans, especially when examining education, gender and age. Study Design Sample was drawn from the Cameron County Hispanic Cohort (CCHC) where participants were randomly selected and completed a survey to report sedentary behavior and perceptions of the environment among other examinations. The participants’ initial visit with the CCHC was included in the …

Understanding The Similarity And Diveristy Of The Accessory Gene Regulator Quorum Sensing Systems In The Genus Clostridium, Rotem Magal

Dissertations and Theses (Open Access)

The Accessory Gene Regulator (Agr) quorum sensing system is a cell-cell communication system that is involved in regulating various bacterial processes such as toxin production, antibiotic production, biofilm formation, and other biomolecules. Despite the importance of the Agr system to Clostridia, the similarity and diversity of the system have been overshadowed by phylum-wide investigations of individual Agr components. To determine the variability of the Agr system within and between Clostridium species, we compared the sequences of its components within and between species using bioinformatics and phylogenetic tools. Putative Agr operons were found in over 50 Clostridia species, including undescribed components …

Predictors Of On-Treatment Mortality Of Patients Undergoing Palliative Radiation Therapy: Improving The Quality Of End-Of-Life Cancer Care, Matthew Stephen Ning

Dissertations and Theses (Open Access)

PURPOSE: Excessive medical treatment at end-of-life is an indicator of poor quality care. While radiation therapy (RT) is effective for palliation, some patients die shortly after or even during treatment. Any treatment that requires terminal patients to spend significant time in the hospital setting contradicts palliative goals. This study investigates patterns of end-of-life RT to inform quality improvement initiatives. METHODS: All patients who died within 6 months of starting RT at a single large academic cancer center between 2015 through 2018 were identified through our institutional databases on an Institutional Review Board-approved protocol. Clinical factors including age, treatment service, number …