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Childhood Trauma And Chronic Disease, Breanna Urena

Graduate Research Projects

No abstract provided.

Further Decoding The Molecular Relationship Between Pancreatic Adenocarcinoma And Diabetes Mellitus, Russell H. Moreland Iii, Sheema Khan

MEDI 9331 Scholarly Activities Clinical Years

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy, especially as there are no current reliable methods of screening. Recently literature reports a significant relationship with pancreatic ductal adenocarcinoma and diabetes mellitus (DM). The pathologic molecular mechanism is not completely understood but it may hold insights into the development of novel screening and treatment options. In our study we compiled a list of 74 proteins involved in the PDAC and DM pathway, with 47 showing increased expression levels and 11 with decreased expression levels. These proteins are currently undergoing further computational analysis to identify their pathway interactions.

Crosstalk Between Hippo And Rb Tumour Suppressor Pathways In Ovarian Cancer, Fatmata Sesay

Theses and Dissertations

The cell cycle is a highly regulated process that ensures the timely and accurate division of cells. Events of the normal cell cycle fall under two categories - positive and negative regulatory mechanisms. The first category, positive regulatory machinery, includes active protein complexes of cyclins in association with their partnering cyclin-dependent kinases (cyclin/CDK), which mediate series of phosphorylation events that relay a cell cycle progression from one stage to the next. The second category, the negative regulatory mechanisms, include the checkpoint controls consisting of the retinoblastoma (RB) family of proteins, some of which can form a transcriptional repressor complex DREAM. …

Anthracyclines Attenuate The Nrf1-Mediated Bounce-Back Response, Bader Albalawi

Theses and Dissertations

Proteasome inhibitors, such as carfilzomib, are FDA-approved to treat multiple myeloma and mantle cell lymphoma. Unfortunately, proteasome inhibitors have only produced clinically significant results in patients with hematologic cancers, despite their predicted pan-cancer utility, and even hematologic cancer types frequently show intrinsic and acquired resistance.

One proposed mechanism responsible for the proteasome inhibitors' shortcomings is the NRF1-mediated bounce-back response. Identification of drugs that can potentiate the action of proteasome inhibitors could overcome resistance in patients with hematologic cancers and expand proteasome inhibitors' use to treat solid tumors. Our previous studies have identified anthracyclines as potential compounds that interfere with the …

Modeling Of Patient-Specific Periaortic Mechanics And Pulmonary Artery Hemodynamics Based On Phase-Contrast Magnetic Resonance Imaging Sequences., Johane H. Bracamonte

Theses and Dissertations

Inverse modeling in cardiovascular medicine is a collection of methodologies that can provide non-invasive patient-specific estimations of clinical risk factors using medical imaging as inputs. Its incorporation into clinical practice has the potential to improve diagnosis and treatment planning with low associated risks and costs.

Herein, three different phase contrast magnetic resonance imaging (MRI) modalities were implemented as input data, displacement encoding with stimulated echoes (DENSE MRI) applied, and time-resolved velocity encoding phase-contrast MRI, in 1D and 3D, applied to pulmonary artery (PA) hemodynamics.

A model to account for the effect of periaortic interactions due to static and dynamic structures …

Alzheimer's Disease Research Progress In Australia: The Alzheimer's Association International Conference Satellite Symposium In Sydney, Claire E. Sexton, Kaarin J. Anstey, Filippo Baldacci, C. J. Barnum, Anna M. Barron, Kaj Blennow, Henry Brodaty, Samantha Burnham, Fanny M. Elahi, Jürgen Götz, Yun-Hee Jeon, Maya Koronyo-Hamaoui, Susan M. Landau, Nicola T. Lautenschlager, Simon M. Laws, Darren M. Lipnicki, Hanzhang Lu, Colin L. Masters, Wendy Moyle, Akinori Nakamura, Giulio Maria Pasinetti, Naren Rao, Christopher Rowe, Perminder S. Sachdev, Peter R. Schofield, Einar M. Sigurdsson

Research outputs 2014 to 2021

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms …

Protocol For The Development Of The International Population Registry For Aphasia After Stroke (I-Praise), M. Ali, A. L. Ben Basat, M. Berthier, M. B. Johansson, C. Breitenstein, D. A. Cadilhac, F. Constantinidou, M. Cruice, G. Davila, M. Gandolfi, M. Gil, R. Grima, Erin Godecke, L. Jesus, L. M. Jiminez, M. Kambanaros, T. Kukkonen, A. Laska, I. Mavis, R. Mc Menamin, C. Mendez-Orellana, H. Obrig, P. Ostberg, H. Robson, K. Sage, M. Van De Sandt-Koenderman, K. Sprecht, E. Visch-Brink, E. Wehling, S. Wielaert, S. J. Wallace, L. J. Williams, M. C. Brady

Research outputs 2014 to 2021

Background: We require high-quality information on the current burden, the types of therapy and resources available, methods of delivery, care pathways and long-term outcomes for people with aphasia. Aim: To document and inform international delivery of post-stroke aphasia treatment, to optimise recovery and reintegration of people with aphasia. Methods & Procedures: Multi-centre, prospective, non-randomised, open study, employing blinded outcome assessment, where appropriate, including people with post-stroke aphasia, able to attend for 30 minutes during the initial language assessment, at first contact with a speech and language therapist for assessment of aphasia at participating sites. There is no study-mandated intervention. Assessments …

Investigating The Influence Of Stress On Motivational Dysfunction In Male And Female Rodents, Emily Laine Errante

Graduate Research Theses & Dissertations

Motivational dysfunction is present in a variety of disorders, including major depressive disorder, schizophrenia, and Parkinsonism and can negatively impact social functioning, employment, and treatment response. Interestingly, outside stressors and stress hormones have been shown to contribute to depressive episodes in humans and depressive-like behaviors in rodents, including reducing motivated behaviors. Effort-related decision making procedures have been utilized in both humans and animals in order to examine motivational dysfunction, as it offers a subject a choice between high effort/reward and low effort/reward options, but little research has examined the effects of stress on effort-related decision making behaviors. Moreover, almost all …

Transgenerational Effects Of Chronic Preconception Stress On Developmental And Health Outcomes In Prairie Vole Offspring: Potential Mediation By Parental Emotionality, Mother-Father Bond, Or Parental Care Quality, W. Tang Watanasriyakul

Graduate Research Theses & Dissertations

Background: A positive rearing environment is important for the health and well-being of growing offspring. Chronic parental stress can create a toxic rearing environment, which may impair developmental and sociobehavioral outcomes of the offspring. Specifically, parental stress is linked to unstable parental emotionality, tension between mother and father, and poor parenting quality, although the inter-relatedness of these factors and the mechanisms through which they contribute to the outcomes of the offspring need further investigation. The current study investigated developmental and sociobehavioral outcomes in prairie vole offspring exposed to chronic preconception stress, with parental emotionality, strength of mother-father bond, and parental …

A Gastrointestinal-Specific Antibiotic As An Experimental Treatment For Anxio-Depressive Disorders, Yuang-Tai Huang

All ETDs from UAB

Chronic stress is a predisposing factor for various disease states, including neuropsychiatric disorders, such as depression and anxiety [1]. Stress-related disorders have complicated multifactorial etiologies [2]. Advances in psychotherapeutic and psychotropic treatments have occurred, but anxiety and depressive disorders are still prevalent and remain a burden to our societies [3]. More than 30% of major depressive disorder patients fail to remission despite an FDAapproved medication [4]. Meanwhile, the contribution of microbiota-gut-brain axis signaling in both etiologies and treatment of stress-related disorders is increasingly being recognized [5]. More evidence has shown that the gut microbiota has the potential to alter the …

Study Of Microrna-23a Cluster In Bone Formation, Revati Suryawanshi

All ETDs from UAB

The differentiation of mesenchymal stem cells to pre-osteoblasts, lies upon various transcription factors and physiological signaling, but is also governed by the micro-RNA-23a cluster. The miR-23a cluster has miR-23a, miR-27a and miR-24-2 transcribed from a single promoter as a sole RNA primary transcript. Its effects have been observed in embryonic stem cells, mesenchymal stem cells (MSCs), and in cancer (1-2). It regulates the lineage commitment of MSCs. (3). With respect to bone formation, miR-23a cluster is involved MSCs commitment to and osteoblast maturation (4). Here, through in vivo and in vitro experiments, we report that knock down of microRNA-23a cluster …

Grainyhead-Like 2 (Grhl2) Has Anti-Oncogenic Potential In Glioblastoma, Rachel M. Carnes

All ETDs from UAB

Grainyhead-like 2 (GRHL2) is a complex transcription factor associated with roles in both development and cancer. In development, GRHL2 suppresses a series of genes associated with the mesenchymal phenotype, while actively promoting the expression of genes associated with the epithelial phenotype. Due to this GRHL2 is considered a main gatekeeper of the epithelial to mesenchymal transition (EMT), playing a crucial role in epithelial morphogenesis and neural tube closure. These basic traits for GRHL2 have also been found to be similar in cancer. GRHL2 has multi-faceted functions in cancer, in which it can be considered either an oncogene or a tumor …

The Role Of Dock3 In Normal Skeletal Muscle Function And Metabolism, Adrienne Samani

All ETDs from UAB

DOCK (dedicator of cytokinesis) are proteins of an 11-member family of typical guanine exchange factors (GEFs) expressed almost exclusively in the brain and spinal cord. Human pathogenic DOCK3 variants have been identified to cause debilitating neuromuscular phenotypes such as muscle hypotonia, ataxia, and intellectual disability. Our lab identified DOCK3 as being strongly upregulated in Duchene muscular dystrophy (DMD), specifically in the skeletal muscles of DMD patient and mouse skeletal muscles. Global Dock3 KO mice on the dystrophin-deficient background exacerbated skeletal muscle and cardiac phenotypes. Similarly, DOCK3 KO mice appeared to have poor muscle architecture, locomotive activity, reduced myogenic fusion, impaired …

Alterations In Synaptic Structure And Tau Phosphorylation In Alheimer's Disease, Courtney K. Walker

All ETDs from UAB

Alzheimer’s disease (AD) is the most common cause of dementia in individuals over the age of 65. Of the two hallmark pathologies of AD, tau neurofibrillary tangles (NFTs) correlate more strongly with cognitive decline than do Aβ plaques. NFTs form in the entorhinal cortex (EC) and appear in anatomically connected regions over time as disease progresses. This tau spreading may occur via synaptic connections. Most excitatory synapses occur on dendritic spines, which house the postsynaptic machinery. Spines are actin-rich, plastic structures that change their size and shape in response to synaptic activity in a process that is dependent on actin …

The Requirement Of Transcriptional Lim Complex Co-Regulators For Pancreatic Endocrine Cell Development And Function, Eliana Davi Toren

All ETDs from UAB

The prevalence and tremendous impact of diabetes mellitus has made glucose regulation of the insulin-producing -cell and surrounding pancreatic islet of Langerhans a center of public and research interests alike. A comprehensive understanding of these hormone-producing cells begins with their developmental origins. What are the genetic cues and participants in the tightly orchestrated process of their formation? Investigating the earliest determinants of islet-cell fate not only allows us to deeply understand mature - and islet-cell function, but also produces a data-driven template for how these cells can be reproduced in future stem-cell based diabetes therapies. LIM transcriptional complexes are indispensable …

Molecular Imaging Of Cancer For Detection And Monitoring Of Response To Combination Therapy, Tiara S. Napier

All ETDs from UAB

Imaging is a primary component of cancer care and aids in diagnosing, response assessment, and monitoring. Molecular imaging techniques provide visualization of unique tumor biology that can be used to personalize treatment. Key features of an effective biomarker are sensitivity, specificity, and ability to provide clinical value beyond that of other types of information already available at the time of diagnosis. For particularly heterogeneous cancer subtypes, such as glioblastoma (GBM) and triple negative breast cancer (TNBC), reliable biomarkers can be challenging to identify and there are few tar-getable receptors for therapy. Our findings demonstrate that quantifying tumor EGFR (panitumumab-IRDye800CW), granzyme …

Restoring The Sphingolipid Balance In Glioblastoma, Cyntanna C. Hawkins

All ETDs from UAB

Glioblastoma (GBM) is a highly aggressive brain tumor with a median survival of 15 months even with standard of care—surgical resection, radiotherapy, and chemotherapy. Two of the key characteristics contributing to this malignancy are its highly invasive phenotype and resistance to the chemotherapy, temozolomide (TMZ). We, and others, have identified the sphingolipid balance as a driver of these phenotypes with dysregulated sphingolipid metabolism seen in GBM patient samples. The ceramidases, specifically acid ceramidase (ASAH1), mediate the balance between ceramides and sphingosine-1-phosphate (S1P). ASAH1 breaks down ceramides ultimately forming S1P. While ceramides induce cell death, S1P promotes migration and cell survival. …

Hedgehog Signaling Rewires M2 Macrophage And Regulatory T Cell Metabolism Within The Tumor Microenvironment Of Breast Cancer, Dominique C. Hinshaw

All ETDs from UAB

Current treatments for breast cancer offer little relief to patients with metastatic disease. A contributory factor to tumor growth and metastasis is aberrant up-regulation of developmental signaling pathways such as the Hedgehog (Hh) signaling pathway. This pathway is aberrantly activated in breast cancer and contributes to tumor progression and metastasis. The success of these events is highly influenced by the surrounding immune microenvironment. Macrophages exist along a spectrum of M1 (tumor-eradicating) to M2 (tumor-promoting), while regulatory T cells (Tregs) are an immunosuppressive cell type. The predominant functions of M2 macrophages and Tregs include dampening the immune response and promoting wound …

Comprehensive Characterization Of Structural Variations Using Long-Read Sequencing Data, Yu Chen

All ETDs from UAB

Structural variants (SVs) contribute to genomic diversity and play pathogenic roles in a wide range of genetic disorders. Accurate characterization of SVs is critical for genomic research and studies of disease mechanisms. The rapid development of Third-Generation Sequencing (TGS) technologies has largely increased sequencing read length compared to Next-Generation Sequencing (NGS), bringing both great potentials and challenges in SV discovery through alignment-based and assembly-based approaches. In order to take full advantage of TGS data, I have developed a suite of bioinformatics tools focusing on comprehensive characterization of SVs. For the alignment-based SV discovery, I have developed DeBreak to identify SVs …

Distinct Clinical Manifestations Associated With Autoantibodies And Cytokines In Systemic Lupus Erythematosus, Fatima K. Alduraibi

All ETDs from UAB

Objective: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by production of autoantibodies (autoAbs) and cytokines. Moreover, lupus nephritis (LN) occurs in approximately 50% of SLE patients. AutoAb and cytokine levels produced by B and T cells are high in LN patients, although their relationship with histological patterns requires investigation. Methods: We analyzed the relationship between B cell cytokines and major T cell cyto-kines, including their association with autoAbs, and the clinical manifestations of SLE, especially LN. We also analyzed endogenous intracellular interferon beta (IFNβ) expression in the peripheral blood mononuclear cells and serum circulating nephritogenic autoAbs from …

The Roles Of Repressive And Activating Epigenetic Factors In Vertebrates Neural And Neural Crest Development, Saeid Mohammad Parast

All ETDs from UAB

The vertebrate nervous system comes from specific regions of the ectoderm that comprises of the neural plate and the neural crest. Although genetic mechanisms governing vertebrate neural development have been investigated in depth, there is a knowledge gap regarding the roles of epigenetic mechanisms in this process. As epigenetic modulators, the COMPASS (also known as SET1/MLL complex) and HP1 proteins are responsible for regulating chromatin accessibility to transcription factors. COMPASS is responsible for deposition of activating histone H3K4 methylation marks at promoters and enhancers and thus creates open chromatin domains. The critical structural and regulatory subunits of COMPASS, Dpy30 and …

Roles Of Chemokine Receptors In T Cell Accmulation In Omental Tumors, Mingyong Liu

All ETDs from UAB

The omentum is an adipose tissue in the peritoneal cavity that contains immune aggregates termed milky spots. Functionally similar to conventional lymphoid tissues, these specialized leukocyte clusters harbor effector and suppressor cells, mount immune responses to antigens, and sustain peritoneal homeostasis. However, the pre-existing leukocytes fail to protect the tissue from tumor colonization. In fact, the omentum is frequently involved in peritoneal metastasis, during which the balance between effector and suppressor immune cells is compromised with the latter gaining dominance. Regulatory T cells (Tregs) represent a major immunosuppressive population in the omentum and rapidly accumulate after tumor implantation. The increased …

Determining The Impact Of Immune Dysregulation On Cd4 T Cell Responses To Hiv-1 And Sars-Cov-2, Jacob K. Files

All ETDs from UAB

CD4+ T cells, often referred to as helper T cells, play a crucial role in the formation of antiviral immune responses following infection and vaccination. However, this can be disrupted by various forms of immune dysregulation. Many groups have described how HIV-1 adaptation and immune escape can lead to dysregulated HIV-specific immune responses. Our lab has previously shown that predicted HLA-II associated HIV-1 adaptation leads to dysregulated, poorly immunogenic CD4+ T cell responses in HIV-1 infection. Here, we focus on the impact of this HLA-II associated viral adaptation in the setting of HIV-1 vaccination. We show that HLA-II associated, vaccine-matched …

The Role Of Protein Translation And Degradation In Aging And Alzheimer Disease Pathogenesis, Harper S. Kim

All ETDs from UAB

Protein translation (PT) is an essential cellular process playing crucial roles in growth and development. PT precipitously declines with age in multiple animal species, including humans. It has been implicitly assumed that elevated PT at young ages is beneficial to health while PT ends up dropping as a passive byproduct of aging. However, whether this holds true and how dynamic fluctuations in PT over time impact aging remain unknown. In Drosophila, we show that a transient PT spike in early-adulthood drives aging by triggering dysfunction in protein homeostasis (proteostasis) at old ages. We propose the early-adulthood spike in PT to …

Understanding The Protumorigenic Functions Of St6gal1 In Glioblastoma Stemness And Metabolism, Sajina Gc

All ETDs from UAB

Glioblastoma (GBM) is a rare but deadly cancer with median survival of just 15 months despite of aggressive treatment. Advancement in novel treatment modalities is hindered by its heterogeneous nature, which includes subsets of neural stem cell-like brain tumor initiating cells (BTICs) that are highly tumorigenic and therapy-resistant. bgalactoside a-2,6-sialyltransferase 1 (ST6Gal1) is elevated in most tumors including in normal and neoplastic stem cells. ST6Gal1 imparts oncogenic phenotypes such as invasion, apoptosis evasion, therapy resistance, TIC maintenance among others via sialylation of critical receptors like, Fas, TNFR1, EGFR and more. Yet ST6Gal1 led regulation of BTIC specific cell surface proteins …

Characterizing The Role Of Tissue-Specific Retinol Dehydrogenases, Kelli Rae Goggans

All ETDs from UAB

The bioactive form of vitamin A, retinoic acid is essential for development, cellular differentiation, epigenetic modifications, the immune system, and a variety of other processes due to its ability to regulate over 500 genes through activation of nuclear receptors. While many studies have focused on characterizing the biosynthesis and signaling of retinoic acid in embryogenesis, few have focused on adult tissues. Recent research has identified a novel retinol dehydrogenase, retinol dehydrogenase epidermal 2 (RDHE2), and shown RDHE2 is a potent, physiologically relevant retinol dehydrogenase in Xenopus. The work in this dissertation characterizes RDHE2 in mammalian models. We identify a paralog …

Transcriptional Regulation Of Metabolism And Synaptic Function In Neurons, Stephanie N. Fox

All ETDs from UAB

Mitochondrial dysfunction, transcriptional dysregulation, and protein aggregation are all unifying features of neurodegenerative disorders, including Parkinson’s Disease. Parkinson’s Disease is a debilitating movement disorder with no known cure, leading sci-entists to explore the underlying etiological contributors to neuronal dysfunction and loss to devise strategies for neuroprotection. Estrogen-related receptor gamma (ERRγ) is a member of a family of transcription factors which regulate the expression of mitochondrial genes. To determine whether ERRγ modulation can provide insight into transcriptional and mitochondrial dysfunction with neurodegeneration, the experiments in this thesis project determined 1) the importance of transcription of mitochondrial genes in disease as regu-lated …

Epigenetic Regulation Of Gene Expression In Temporal Lobe Epilepsy, Rebecca Mary Hauser

All ETDs from UAB

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is characterized by seizures originating from the temporal lobe of the brain. A frequent seizure focus in TLE is the hippocampus, a structure located within the temporal lobe crucial for its role in memory formation. Seizures are an excess of synchronous excitation in the brain caused by a surplus of excitatory neurotransmission and a lack of sufficient inhibitory transmission. Coordinating the process of neuronal transmission is differential expression of genes likely resulting in an increase or decrease in proteins responsible for neural signaling such as neurotransmitters, ion …

Il-2-Mediated Stat3 Activation Controls Effector T Regulatory Cell Development, Emma C. Dean

All ETDs from UAB

Heterogeneity in phenotype and function of Treg cells is becoming increasingly appreciated, especially in the context of creating potent Treg cell–based therapeutics in the treatment of inflammatory bowel disease. One of the barriers to developing such therapeutics is the limited understanding of the signals that play a role in the development of Treg cell subsets. Here, we found STAT3 signaling to be enriched in induced IL-10 competent Treg (iTreg) cells in the colon. Through the development of a new in vitro system, we found that STAT3 was required for proper development of IL-10 competent iTreg cells and that IL-2 regulated …

Epigenetic Regulation By O-Glcnac Alters Anti-Fibrotic Gene Expression In Ipf Fibroblasts, Qiuming Wu

All ETDs from UAB

Idiopathic pulmonary fibrosis (IPF) is an age-related chronic disease with a me-dian survival period of 3-4 years [1]. Although FDA has approved two drugs that may slow the disease process, there is no effective treatment [2]. IPF is characterized by the excessive deposition of collagen, which leads to deformation of alveolar structure, loss of lung function, and ultimately death [3]. Anti-fibrotic genes such as cyclooxygenase-2 (COX-2) and Heme Oxygenase 1 (HMOX-1) are usually suppressed in the pathogenesis of IPF [4-6], while the mechanisms responsible for the repression of anti-fibrotic genes in IPF are incompletely understood. More evidence has shown that …