Cell Biology Commons^™

Identifying A Glucocorticoid-Activated Gpcr That Rapidly And Non-Genomically Increases Camp Levels In Mammalian Cells, Francisco Nunez

Pharmaceutical Sciences (PhD) Dissertations

Glucocorticoids (GCs) are steroid hormones that regulate diverse physiological processes. Synthetic versions of GCs are commonly used to treat inflammatory diseases such as asthma by modulating gene expression to suppressing several inflammatory activities. However, it is estimated that 5-10% of asthmatics are unresponsive to GCs, which may be explained by receptor desensitization and/or the presence of a neutrophilic endotype. One understudied phenomenon of GCs is their ability to induce rapid, non-genomic actions. For example, GCs can acutely modulate calcium concentrations levels, induce smooth muscle relaxation and modulate nitric oxide synthase activity, within minutes and sometimes seconds, which is too rapid …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

The Effect Of Fibrodysplasia Ossificans Progressiva On The Tongue, Amy Backal, Amanda Harrop, David J. Goldhamer Dr.

University Scholar Projects

FOP is a rare genetic disorder in which skeletal muscle and associated connective tissue progressively turn to bone through a process called heterotopic ossification (HO). The extra skeletal bone growth is cumulative, eventually trapping patients in a second skeleton that eventually leads to death by asphyxiation. The FOP mutation is autosomal dominant that can be inherited or acquired sporadically. Unfortunately, FOP is currently incurable with no therapeutic options to inhibit bone growth or reduce existing bone nodules. My project intends to further our understanding of the cellular mechanisms of the disease within the tongue muscle. A population of cells known …

The Effect Of Fibrodysplasia Ossificans Progressiva On The Tongue, Amy Backal, Amanda Harrop, David J. Goldhamer Dr.

Honors Scholar Theses

FOP is a rare genetic disorder in which skeletal muscle and associated connective tissue progressively turn to bone through a process called heterotopic ossification (HO). The extra skeletal bone growth is cumulative, eventually trapping patients in a second skeleton that eventually leads to death by asphyxiation. The FOP mutation is autosomal dominant that can be inherited or acquired sporadically. Unfortunately, FOP is currently incurable with no therapeutic options to inhibit bone growth or reduce existing bone nodules. My project intends to further our understanding of the cellular mechanisms of the disease within the tongue muscle. A population of cells known …

Resolving The Repression Pathway Of Virulence Gene Hila In Salmonella, Alexandra King, Lon Chubiz Phd, Brenda Pratte, Lauren Daugherty

Undergraduate Research Symposium

Salmonella is a relatively abundant, virulent species of bacteria that is most known for spreading gastrointestinal diseases through food. These illnesses result in approximately 1.35 million infections, including over 25,000 hospitalizations each year, in the U.S. alone (CDC.gov). As antibiotic resistance becomes an increasingly urgent public health problem, the importance of developing alternative treatment methods is only becoming more crucial. One of the genes responsible for this virulence is known as hilA. HilA is the main transcriptional regulator of Salmonella Pathogenicity Island-1 gene (UniProt). SPI-1 plays an important role in the invasion of Salmonella into epithelial cells. The proteins encoded …

Characterization Of 1,1-Diarylethylene Foxm1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells, Cassie Liu

Theses & Dissertations

Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases, and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell …

Cannabinoids And Retinal Fibrotic Disorders., Lucy June Sloan

Electronic Theses and Dissertations

Retinal fibrosis is detrimental to vision. Retinal pigment epithelial (RPE) cells contribute to several retinal fibrotic diseases. Upon exposure to TGF-β, a key fibrotic cytokine, RPE cells trans-differentiate to myofibroblasts marked by the integration of α-SMA fibers into F-actin stress fibers, which confer strong contractility. Myofibroblasts produce and contract the collagen-rich fibrotic scar and disrupt retinal architecture. In this study, we investigated the in vitro effects of the putative endocannabinoid compound N-oleoyl dopamine (OLDA) on TGF-β2 induced porcine RPE cell contraction and α-SMA expression. Using an in vitro collagen matrix contraction assay, we found that OLDA inhibited TGF-β2 induced contraction …

Investigating The Role Of The Basolateral Amygdala Plays In The Incubation Of Cue-Induced Cocaine Seeking Behavior, Claire Marie Corbett

Graduate School of Biomedical Sciences Theses and Dissertations

Cocaine use disorder is a chronic, relapsing brain disease. Sex and ovarian hormones are known to influence cocaine addiction liability and relapse vulnerability. However, little is known regarding the cellular and synaptic mechanisms contributing to sex differences in relapse vulnerability, including how these measures are influenced by hormonal fluctuations. To investigate sex differences in relapse vulnerability we use a rodent model of cocaine craving and relapse called the incubation model in which cue-induced seeking progressively increases or “incubates” during the first month of withdrawal from extended-access cocaine self-administration. Using this model, we have recently shown that females in the estrus …

Paratesticular Solitary Fibrous Tumour Mimicking Cellular Angiofibroma: An Unusual Morphology And Rare Site, Madiha Bilal Qureshi, Muhammad Usman, Qurratulain Chundriger, Nasir Uddin

Department of Pathology and Laboratory Medicine

Solitary fibrous tumour (SFT) is a ubiquitous benign mesenchymal tumour of fibroblastic origin, which occurs most often in middle-aged adults. It usually presents as lung mass originating from pleura, but extrapleural occurrence is also common. Tumour is characterised by hypo- and hyper-cellular areas of spindle-shaped cells, arranged in haphazard manner with dispersed staghorn-shaped vessels. Surgical excision is the curative treatment. SFTs of the primary testicular or paratesticular region are extremely rare, but they exhibit histologic findings similar to SFTs originating at other body sites. Here, we report the case of a paratesticular SFT in a 37-year male, who presented with …

Cilia Proteins Are Biomarkers Of Altered Flow In The Vasculature, Ankan Gupta, Karthikeyan Thirugnanam, Madhan Thamilarasan, Ashraf M. Mohieldin, Hadeel T. Zedan, Shubhangi Prabhudesai, Meghan R. Griffin, Andrew D. Spearman, Amy Pan, Sean P. Palecek, Huseyin C. Yalcin, Surya M. Nauli, Kevin R. Rarick, Rahima Zennadi, Ramani Ramchandran

Pharmacy Faculty Articles and Research

Cilia, microtubule-based organelles that project from the apical luminal surface of endothelial cells (ECs), are widely regarded as low-flow sensors. Previous reports suggest that upon high shear stress, cilia on the EC surface are lost, and more recent evidence suggests that deciliation—the physical removal of cilia from the cell surface—is a predominant mechanism for cilia loss in mammalian cells. Thus, we hypothesized that EC deciliation facilitated by changes in shear stress would manifest in increased abundance of cilia-related proteins in circulation. To test this hypothesis, we performed shear stress experiments that mimicked flow conditions from low to high shear stress …

Conformational Flexibility And Local Frustration In The Functional States Of The Sars-Cov-2 Spike B.1.1.7 And B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism Of Functional Dynamics And Protein Stability, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structural and functional studies of the SARS-CoV-2 spike proteins have recently determined distinct functional states of the B.1.1.7 and B.1.351 spike variants, providing a molecular framework for understanding the mechanisms that link the effect of mutations with the enhanced virus infectivity and transmissibility. A detailed dynamic and energetic analysis of these variants was undertaken in the present work to quantify the effects of different mutations on functional conformational changes and stability of the SARS-CoV-2 spike protein. We employed the efficient and accurate coarse-grained (CG) simulations of multiple functional states of the D614G mutant, B.1.1.7 and B.1.351 spike variants to characterize …

The Effects Of Neuronal Growth Factors On Lps-Activated Schwann Cells, Caitlyn E. Henry, Peyton Kimmel, Angela Asirvatham Ph.D.

Student Research Poster Presentations 2022

Schwann cells (SCs) are the principal support cells of neurons in the peripheral nervous system, that both myelinate axons for the rapid conduction of electrical impulses as well as assist in axonal repair during nerve injury. During nerve injury, SCs secrete tumor necrosis factor alpha (TNF-α)^1,5,6 and other proinflammatory mediators^1,6, attracting macrophages to the site of injury to induce inflammation and clear myelin debris.^1,6 Once the debris is cleared, the neuron stimulates SC proliferation by secreting neuronal mitogens, such as heregulin^3,4, and an unknown factor that activates the cAMP pathway³, an important …

Simulation Of An Inflammatory Model Using Schwann Cells, Caitlyn Henry, Peyton Kimmel, Angela Asirvatham

Student Research Poster Presentations 2022

During peripheral nerve injury, the myelin surrounding the neuronal axons is damaged, initiating an inflammatory response to remove myelin debris. Once myelin debris is cleared, Schwann cells acquire a proliferating phenotype which allows them to grow and divide so that remyelination can occur. The neuron stimulates Schwann cell division by secreting growth factors, like heregulin, and an unknown growth factor that activates the cAMP pathway. Although the role of cAMP in axonal regeneration is well-known, not much has been explored about its function in Schwann cells during nerve injury and inflammation. To simulate an inflammatory environment, the S16 Schwann cell …

Novel Biomarkers Of Ciliary Extracellular Vesicles Interact With Ciliopathy And Alzheimer’S Associated Proteins, Ashraf M. Mohieldin, Amal Alachkar, John R. Yates Iii, Surya M. Nauli

Pharmacy Faculty Articles and Research

Ciliary extracellular vesicles (ciEVs), released from primary cilia, contain functional proteins that play an important role in cilia structure and functions. We have recently shown that ciEVs and cytosolic extracellular vesicles (cyEVs) have unique and distinct biomarkers. While ciEV biomarkers have shown some interactions with known ciliary proteins, little is known about the interaction of ciEV proteins with proteins involved in ciliopathy and neurodegenerative disorders. Here, we reveal for the first time the protein-protein interaction (PPI) between the top five ciEVs biomarkers with ciliopathy and Alzheimer disease (AD) proteins. These results support the growing evidence of the critical physiological roles …

Novel Approaches For Enhancing Cell Survival And Function In Vivo, Ou Wang

Department of Chemical and Biomolecular Engineering: Dissertations, Theses, and Student Research

FDA has approved several cell-based therapeutics and hundreds of cell therapy clinical trials are ongoing. Cells will be a significant type of medicine after small molecule and protein drugs. However, several obstacles need to be addressed to achieve the widespread use of cellular therapeutics. The first challenge is the low efficacy of cell transplantation due to low retention, survival, integration, and function of cells in vivo. The second challenge is producing a massive number of cells for clinical treatment with cost-effectively and reproducibly technologies.

In this thesis, we proposed and investigated two approaches to address these challenges. To begin …

Differentiating The Mechanistic Role And Chemotherapeutic Potential Of Src And Podoplanin In Oncogenic Transformation, Edward P. Retzbach

Graduate School of Biomedical Sciences Theses and Dissertations

There were an estimated 20 million new cancer cases worldwide in 2020, resulting in nearly 1000 deaths per hour [1]. Oral cancer exemplifies the difficulties of treating cancer patients. The first line for oral cancer treatment is surgery and radiation that can lead to patient disfigurement and decreased quality of life in cancer survivors [2-4]. Though there have been many developments in chemotherapy in the last 30 years, the 50% mortality rate associated with oral cancer has not changed [4, 5]. Longitudinal studies that track survival rates in oral cancer patients demonstrate a 3-fold reduction in patient deaths when patients …

4d Ex Vivo Crispr/Cas9 Whole-Genome Screen To Identify Genes Regulating Lung Cancer Metastasis, Alexandria Plumer

Dissertations and Theses (Open Access)

Metastatic lung cancer has a 5-year survival rate of 5%. Lung cancers tend to be asymptomatic until late stages, and almost 90% are not diagnosed until they are advanced. Metastases are very rare events, often initiated by a single cell from a primary tumor into a new niche at a distant location. Investigation of the early metastatic process is of urgent need for the development of early diagnostics and targeted therapeutics. We performed a proof-of-concept CRISPR/Cas9 whole genome knockout screen in the A549 lung adenocarcinoma cell line and utilized a novel ex vivo 4D lung metastasis model to find gene …

Lgr5 Regulation Of Stat3 Signaling And Drug Resistance In Colorectal Cancer, Tressie Posey, Tressie Alexandra Posey

Dissertations and Theses (Open Access)

LGR5 Regulation of STAT3 Signaling and Drug Resistance in Colorectal Cancer

Tressie Alexandra Capri Posey B.S.

Advisory Professor: Kendra Carmon, Ph.D.

The greatest difficulty in treating colorectal cancer (CRC) is the development of drug resistance which leads to relapse after treatment and progression to metastasis. Cancer stem cells (CSCs) are believed to drive relapse because of their capacity to self-renew, acquire resistance mechanisms, and differentiate promoting tumor growth and heterogeneity. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), is a bona-fide marker of CSCs and has been considered a viable target for CSC specific therapeutic development. While we showed targeting LGR5 …

Epithelial Memory Of Resolved Inflammation Limits Tissue Damage While Promoting Pancreatic Tumorigenesis, I-Lin Ho

Dissertations and Theses (Open Access)

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma. When occurring in the context of pancreatitis, mutations of KRAS accelerate tumor development. We discovered that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, epithelial cells of the pancreas display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the prompt reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thus efficiently limiting tissue damage via rapid decrease of zymogen production. We propose that since activating mutations of KRAS …

Suppression Of Dc-Sign And Gh Reveals Complex, Subset-Specific Mechanisms For Kshv Entry In Primary B Lymphocytes, Nancy Palmerin, Farizeh Aalam, Romina Nabiee, Murali Muniraju, Javier Gordon Ogembo, Jennifer Totonchy

Pharmacy Faculty Articles and Research

Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of multiple cancers in immunocompromised patients including two lymphoproliferative disorders associated with KSHV infection of B lymphocytes. Despite many years of research into the pathogenesis of KSHV associated diseases, basic questions related to KSHV molecular virology remain unresolved. One such unresolved question is the cellular receptors and viral glycoproteins needed for KSHV entry into primary B lymphocytes. In this study, we assess the contributions of KSHV glycoprotein H (gH) and the cellular receptor DC-SIGN to KSHV infection in tonsil-derived B lymphocytes. Our results show that (1) neither KSHV-gH nor DC-SIGN are essential …

Directed Genome Evolution To Identify Genes For Macrophage Survival By Staphylococcus Agnetis, Sonali Lakshika Anne Lenaduwe Lokuge

Graduate Theses and Dissertations

Bacterial Chondronecrosis with Osteomyelitis (BCO) is a debilitating infection that negatively impacts animal welfare and costs the broiler industry billions of dollars annually. We have previously isolated Staphylococcus agnetis 908 from BCO samples obtained from broilers at the University of Arkansas research farm. This isolate can induce BCO lameness at greater than 50% in broilers exposed to the pathogen in drinking water. We found that S. agnetis 908 is capable of surviving and escaping macrophages compared to a closely related cattle isolate,1379. Through Directed Genome Evolution (DGE) we identified that this difference is at least partially associated with an alanine …

Identifying The Cell Composition And Clonal Diversity Of Supratentorial Ependymoma Using Single Cell Rna-Sequencing, James He

University Scholar Projects

Ependymoma is a primary solid tumor of the central nervous system. Supratentorial ependymoma (ST-EPN), a subtype of ependymomas, is driven by an oncogenic fusion between the ZFTA and RELA genes in 70% of cases. We introduced this fusion into neural progenitor cells of mice embryos via in utero electroporation of a non-viral binary piggyBac transposon system containing ZFTA-RELA. From preliminary data in the LoTurco lab, inducing the expression of ZFTA-RELA into different neural progenitor cells produces tumors of varying lethality and cellular composition. To define the cellular composition and subclonal diversity of ST-EPN tumors, we used single cell RNA-sequencing to …

The Effects Of Mapk Signaling On The Development Of Cerebellar Granule Cells, Kerry Morgan

University Scholar Projects

The granule cells are the most abundant neuronal type in the human brain. Rapid proliferation of granule cell progenitors results in dramatic expansion and folding of the cerebellar cortex during postnatal development. Mis-regulation of this proliferation process causes medulloblastoma, the most prevalent childhood brain tumor. In the developing cerebellum, granule cells are derived from Atoh1-expressing cells, which arise from the upper rhombic lip (the interface between the roof plate and neuroepithelium). In addition to granule cells, the Atoh1 lineage also gives rise to different types of neurons including cerebellar nuclei neurons. In the current study, I have investigated the …

The Effects Of Mapk Signaling On The Development Of Cerebellar Granule Cells, Kerry Morgan

Honors Scholar Theses

The granule cells are the most abundant neuronal type in the human brain. Rapid proliferation of granule cell progenitors results in dramatic expansion and folding of the cerebellar cortex during postnatal development. Mis-regulation of this proliferation process causes medulloblastoma, the most prevalent childhood brain tumor. In the developing cerebellum, granule cells are derived from Atoh1-expressing cells, which arise from the upper rhombic lip (the interface between the roof plate and neuroepithelium). In addition to granule cells, the Atoh1 lineage also gives rise to different types of neurons including cerebellar nuclei neurons. In the current study, I have investigated the …

Search For Palladin, An Actin-Associated Protein, In Pig Retinal Pigmented Epithelium And Its Role In Epithelial-Mesenchymal Transition, Katrina Powell

Undergraduate Theses

This study investigates the expression of Palladin, a phosphoprotein product of the PALLD gene, in the retinal pigmented epithelium (RPE). Palladin is an actin cross-linking protein and plays a role in cell adhesion and motility. Published reports have demonstrated that a down regulation of Palladin in colon cancer cells results in a reorganization of the actin cytoskeleton, causing the cells to lose their typical shape, become proliferative and migratory. This process is otherwise known as epithelial-mesenchymal transition (EMT). A similar EMT phenomenon is observed when the RPE is exposed to the vitreous humor in patients with proliferative vitreoretinopathy (PVR). In …

The Dopamine D3 Receptor Antagonist Vk4-40 Attenuates Morphine-Induced Hyperactivity But Not Cocaine-Induced Hyperactivity In Mice, Desta M. Pulley, Jessica J. Debski, Daniel Manvich

Rowan-Virtua Research Day

In light of the increasing rates of opioid abuse in the US, the search for viable medications to treat opioid abuse disorder (OUD) has become ever more urgent. Opioids exert their abuse-related effects in part by indirectly increasing dopamine (DA) neurotransmission in the mesolimbic system, a dopaminergic projection arising in the ventral tegmental area and terminating in the nucleus accumbens. The DA D3 receptor (D3R), which belongs to the D2 family of dopamine receptors (D2, D3 , D4 receptor subtypes), is highly expressed in these brain regions and has shown strong potential as a pharmacotherapeutic target for the treatment of …

Mitochondrial Distribution Of Glycine Receptors In Motor Neuron Cell Lines, Katsiaryna Milashevich

Student Theses and Dissertations

Although non-essential, glycine plays an important role in major metabolic reactions and is most known for its anti-inflammatory effects. An accumulation of contemporary research has shown that glycine is able to stabilize membrane potential using glycine receptors at the cellular level and to protect mitochondrial function directly, whether it is from inflammation, heavy metal poisoning, or ischemia-induced neuroinflammation. In this research, the existence of a hypothetical mitochondrial glycine receptor is examined. Immunofluorescence imaging was used to examine the presence of the glycine receptor subunits alpha 1 and alpha 2 in both non- differentiated and differentiated neuroblastoma cell lines. The preliminary …

Review: The Bidirectional Relationship Between Mitochondrial Respiratory Chain Inhibition And Import Machinery Malfunction In Parkinson’S Disease, Grace Riggs, Deepa Dabir

Honors Thesis

Parkinson’s Disease (PD) is characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) portion of the ventral midbrain, the region of the brain largely responsible for motor control, executive cognitive function, and emotional limbic activity (Sonne 2020). SNpc dopaminergic neurons are more vulnerable than those in other regions due to their high energy demand arising from long, highly branched, unmyelinated axons (Pissadaki & Bolam 2013). They also have a higher basal rate of oxidative phosphorylation, which has been hypothesized to further increase vulnerability in cases of PD (Pacelli et al., 2015). One of the major …

022— Examining P27 Expression And Quiescence In Clobetasol-Exposed Umscv-4 Vulvar Cancer Cells, Nina Mustico, Vincent Scalcione, Jani E. Lewis

GREAT Day Posters

Vulvar cancer is rare, mostly afflicting women aged 60 and older [1]. The cancer is often preceded by a common vulvar rash, lichen sclerosus, that is usually treated with the ultra-potent corticosteroid, clobetasol propionate. This treatment may, in turn, be associated with vulvar carcinogenesis. Our previous findings suggest that clobetasol is causing UMSCV-4 vulvar carcinoma cells to enter a state of quiescence. Quiescence is temporary removal from the cell cycle and can be thought of as a dormant state in which cells are not actively dividing [2]. There is growing evidence suggesting that quiescence may play a role in allowing …

Long-Term Impacts Of Acute Stressor Exposure On Locus Coeruleus Function And Anxiety-Like Behavior In Rats, Olga Borodovitsyna

Graduate School of Biomedical Sciences Theses and Dissertations

Stress is a physiological state characterized by behavioral arousal that occurs during exposure to harmful or threatening stimuli, and usually facilitates an adaptive behavioral response. The persistence of stress sometimes causes it to become maladaptive, potentially contributing to disease development, including physiological complications with altered neuroendocrine signaling and impaired function of organ systems, and psychological conditions including depression and anxiety. Anxiety disorders in particular are associated with a history of stress and are the most common class of mental disorders, with a lifetime prevalence of 33.7% in the general population. The locus coeruleus (LC) is a major node in the …