Medical Cell Biology Commons^™

Arl2bp, A Novel Ciliopathy Protein, Is Required For Cilia Microtubule Formation, Abigail Ruth Moye

Graduate Theses, Dissertations, and Problem Reports (ETD)

Cilia are specialized organelles essential for cellular function. Not surprisingly, mutations in cilia- related genes are linked to multi-syndromic diseases termed ciliopathies. These include blinding diseases such as retinitis pigmentosa (RP). One such novel gene is ARL2BP (ARL2-binding protein) and is linked to RP and situs inversus (organ reversal) in humans, a phenotype produced by defects in the nodal cilia of developing embryos. Defects in photoreceptor cilia, as well as situs inversus in human patients, suggest that ARL2BP plays an invaluable role in the structure and function of cilia. However little is known about the role for this protein in …

The Role Of Yes-Associated Protein 1 In Ovarian Physiology And Pathology, Xiangmin Lv

Theses & Dissertations

Ovarian granulosa cells are the major somatic components of the ovarian follicle. Proper proliferation and differentiation of ovarian granulosa cells are essential for successful follicle development. Accumulating evidence indicates that the Hippo-YAP signaling pathway plays critical roles in both development and tumorigenesis of several organs. The present study aims to investigate the role of Yes-associated protein 1 (YAP) in ovarian granulosa cell proliferation, differentiation, and malignant transformation. At first, we found that nuclear YAP (active) was highly expressed in proliferative granulosa cells, whereas cytoplasmic YAP (inactive) was detected mainly in terminally-differentiated luteal cells. Further studies suggested that endogenous YAP activity …

Novel Therapeutic Strategies For Treatment Of Castration-Resistant Prostate Cancer, Matthew A. Ingersoll

Theses & Dissertations

Prostate cancer (PCa) remains the most commonly diagnosed solid tumor and is the third leading cause of cancer-related death in United States men. While androgen deprivation therapy is the current standard-of-care treatment for metastatic PCa, most patients eventually relapse and develop castration-resistant (CR) tumors, for which there is currently no effective treatment. Therefore, synthesis of novel therapeutic agents and identification of alternative target proteins are necessary to improve treatment. Herein, I investigate the efficacy of novel imidazopyridine and statin derivatives as alternative therapeutic compounds. These molecules not only inhibit androgen receptor signaling, but also block activation of the AKT axis, …

Niche Cadherins Control The Quiescence-To-Activation Transition In Muscle Stem Cells., Aviva J. Goel, Marysia-Kolbe Rieder, Hans-Henning Arnold, Glenn L. Radice, Robert S. Krauss

Department of Medicine Faculty Papers

Many adult stem cells display prolonged quiescence, promoted by cues from their niche. Upon tissue damage, a coordinated transition to the activated state is required because non-physiological breaks in quiescence often lead to stem cell depletion and impaired regeneration. Here, we identify cadherin-mediated adhesion and signaling between muscle stem cells (satellite cells [SCs]) and their myofiber niche as a mechanism that orchestrates the quiescence-to-activation transition. Conditional removal of N-cadherin and M-cadherin in mice leads to a break in SC quiescence, with long-term expansion of a regeneration-proficient SC pool. These SCs have an incomplete disruption of the myofiber-SC adhesive junction and …

Understanding The Chondrogenic Potential Of Articular Chondrocytes, Krishna Sarma

Theses & Dissertations

Articular cartilage is a smooth, visco-elastic, aneural, avascular tissue made of water, an exquisitely organized framework of proteoglycans, glycosaminoglycans, and collagen fibrils and articular chondrocytes. It’s beautiful organization and composition provide it with the flexibility and strength to cover, protect and lubricate the ends of long bones in a diarthrodial joint. Cartilage homeostasis relies on articular chondrocytes to translate the mechanical forces of daily activity into efficient remodeling of the extracellular matrix. Age, joint injury, or other insulting factors can progressively incapacitate articular chondrocytes, resulting in cartilage lesions that devolve to degenerative joint disease. Therefore, the central idea explored in …

Finding Human Proteins That Bind To A Lassa Virus Protein, Maria Alejandra Pardo Ruge, Veronica J. Heintz, Douglas J. Lacount

The Summer Undergraduate Research Fellowship (SURF) Symposium

Viral hemorrhagic fevers are severe illnesses caused by many different viruses. Lassa Virus is one of these important pathogens in Western Africa, causing hemorrhagic fever and eventually death without early medical treatment. There is no vaccine and there is little information on host-pathogen interactions. Therefore, the interaction between viral proteins and host targets is useful to understand Lassa virus’s lifecycle and pathology, and to develop ways to prevent infection. In this project, we study the nucleoprotein of Lassa virus (NP), which has been reported to have anti-interferon (IFN) activity through elimination of double stranded RNA (dsRNA). These features could be …

Ubqln1 : A Multi-Domain Protein With Multiple Functions., Zimple Kurlawala

Electronic Theses and Dissertations

There are 5 Ubiquilin proteins (UBQLN1-4, UBQLN-L), which are evolutionarily conserved and structurally similar. UBQLN proteins have 3 functional domains: N-terminal ubiquitin-like domain (UBL), C-terminal ubiquitin-associated domain (UBA) and STI chaperone-like regions in the middle. Alterations in UBQLN1 gene have been detected in a variety of disorders including Alzheimer’s disease, Amyotropic Lateral Sclerosis and lung cancer. UBQLN1 has been largely studied in neurodegenerative disorders in the context of protein quality control. Several studies have hypothesized that the UBA domain of UBQLN1 binds to poly-ubiquitin chains of substrate and shuttles it to the proteasome via its UBL domain for degradation. UBQLN1 …

Genome-Scale Precision Proteomics Identifies Cancer Signaling Networks And Therapeutic Vulnerabilities, Hong Wang

Theses and Dissertations (ETD)

Mass spectrometry (MS) based-proteomics technology has been emerging as an indispensable tool for biomedical research. But the highly diverse physical and chemical properties of the protein building blocks and the dramatic human proteome complexity largely limited proteomic profiling depth. Moreover, there was a lack of high-throughput quantitative strategies that were both precise and parallel to in-depth proteomic techniques. To solve these grand challenges, a high resolution liquid chromatography (LC) system that coupled with an advanced mass spectrometer was developed to allow genome-scale human proteome identification. Using the combination of pre-MS peptide fractionation, MS2-based interference detection and post-MS computational interference correction, …

Role Of Dendritic Cells In Pathology Of Respiratory Syncytial Virus Infection In Neonates, Bishwas Shrestha

Theses and Dissertations (ETD)

Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children. We have shown that neonatal mice respond to primary RSV infection with T helper type 2 (Th2) biased immune responses, which are enhanced following reinfection. Dendritic cells (DCs) including myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) play important roles in driving host responses to RSV infection. mDCs present antigens to help Th cells differentiate, and pDCs protect against viral infection through type I interferons (IFNs). Despite data demonstrating importance of mDCs and pDCs in protection against RSV, it has not been studied in an age appropriate …

Characterization Of Malt1 Inhibitors And Their Effect On Leukemic Cell Growth Properties, Christina Snyder

Graduate School of Biomedical Sciences Theses and Dissertations

Leukemia is the most common childhood cancer, with a combined 40,000 predicted new cases in the United States in 2016 [8]. The two most common subtypes are acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) [9-11]. The commercially available inhibitor of Bruton’s tyrosine kinase (BTK) has shown promising results in clinical trials for CLL because of the importance of BCR signaling in CLL [12-15]. Recent studies suggest that the outgrowth of BTK inhibitor resistant clonal cells in some CLL patients results in a treatment-refractory phenotype [16-18]. MALT1, a protein involved in BCR activation of the NF-κB pathway that functions …

Targeting Hepatocellular Carcinoma Through Tgf-Β Pathway E3 Ligases, Kazufumi Ohshiro, Jian Chen, Shulin Li, Jon White, Asif Rashid, Lopa Mishra

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

An Rnai Screen To Identify Components Of A Polyamine Transport System, Adam J. Foley

Honors Undergraduate Theses

Polyamines, specifically putrescine, spermidine, and spermine, are small cationic molecules found in all organisms. Cells can biosynthetically make these molecules, or alternatively, they can be transported from the extracellular environment. Malignant cells have been shown to require relatively high amounts of polyamines. There is a chemotherapeutic agent, DFMO, used to block the biosynthesis of polyamines. Many malignant cells can circumvent DFMO therapy by activating their transport system. A potential solution is to simultaneously block biosynthesis and transport of polyamines. However, little is known about the polyamine transport system in higher eukaryotes.

This thesis aims to add to the basic biological …

Telomerase Reverse Transcriptase In Atherosclerosis, Hua Qing

Theses and Dissertations--Pharmacology and Nutritional Sciences

Telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase and the limiting factor for the enzyme activity. The expression of TERT and telomerase activity is increased in atherosclerotic plaques. However, the role of TERT dysregulation during atherosclerosis formation remains unknown.

The work herein first identified a multi-tiered regulation of TERT expression in smooth muscle cells (SMC) through histone deacetylase (HDAC) inhibition. HDAC inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein abundance through enhanced degradation, which decreases telomerase activity and induces senescence. Furthermore, during vascular remodeling in vivo, TERT protein …

The Role Of E. Coli Transcript-Cleavage Factors Gre In Transcriptional Regulation Under Hyperosmotic Stress, Kseniya Obraztsova

Graduate School of Biomedical Sciences Theses and Dissertations

Escherichia coli adapts to changes in the osmotic environment through the process of osmotic response which entails synthesis of specific enzymes and transporters to accumulate essential osmoprotectants. This process is highly regulated at the level of transcription. Upon cell exposure to high salt, RNA polymerase (RNAP} rapidly dissociates from genomic DNA, while the nucleoid becomes hyper condensed. During the subsequent osmoadaptation phase RNAP reassociates with the DNA and resumes transcription. The mechanisms of transcription initiation, promoter escape and its regulation during osmoadaptation are poorly understood. Here we demonstrate that a highly conserved bacterial regulator, transcript cleavage factor GreA, is essential …

Regulation Of Breast Cancer Initiation And Progression By 14-3-3zeta, Chia-Chi Chang

Dissertations and Theses (Open Access)

14-3-3ζ is a ubiquitously expressed family member of proteins that have been implicated to have oncogenic potential through its interactions and involvement in cancer initiation and progression. 14-3-3ζ belongs to the highly conserved 14-3-3ζ protein family and modulates numerous pathways in cancer. Overexpression of 14-3-3ζ is an early event, occurs in more than 40% of human breast cancer cases, and is associated with disease recurrence and poor prognosis. Metabolic reprogramming is a hallmark of cancer. Cancer cells elevate aerobic glycolysis to produce metabolic intermediates and reducing equivalents, thereby facilitating cellular adaptation to the adverse environment and sustaining fast proliferation. Interestingly, …

Development Of Rational Combination Therapy With Parp Inhibitors And Kinase Inhibitors In Tnbc, Wen-Hsuan Yu

Dissertations and Theses (Open Access)

Poly (ADP-ribose) polymerase inhibitors (PARPi) emerge as potential targeting drugs for BRCA-deficient cancers including triple negative breast cancer (TNBC). However, it has been reported that a subgroup of patients even with BRCA mutation fails to respond to PARPi in multiple clinical trials. In this study, we identified c-Met, a tyrosine kinase, phosphorylates PARP1 at Y907 and that the phosphorylation increases PARP1 activity, thereby rendering cancer cells resistant to PARPi. The combination of c-Met inhibitors (METi) and PARPi has a synergistic effect for c-Met overexpressed TNBC in vitro and in vivo. In addition to c-Met, through functional analysis, we found …

Multiphoton Imaging Of Labeled Breast Cancer Cells To Quantify Intra And Extracellular Receptors, Sydney C. Wiggins

Biomedical Engineering Undergraduate Honors Theses

Every year 200,000 women in the United States are diagnosed with breast cancer. Of the cases diagnosed, 10% -15% are classified as triple negative breast cancer (TNBC) due to the absence of estrogen, progesterone, and HER-2/Neu receptors. This breast cancer sub-type is markedly more aggressive and twice as likely to develop in premenopausal women. TNBC is resistant to endocrine therapies and current targeted agents, making clinical need for the development of validated therapeutics for TNBC a pressing matter. To initiate drug development, the internalization of directly immunolabeled epidermal growth factor receptors (EGFR) in SK-BR-3 human breast adenocarcinoma cells was quantitated …

Investigating The Regulation And Function Of The Nr4a Nuclear Receptors In Cancer, Jordan A. Beard

Theses and Dissertations (ETD)

The nuclear receptor (NR) superfamily represents a structurally-conserved group of ligand-regulated transcription factors. These proteins have critical roles in various physiological and pathological processes, including cancer, and have been targets of drug therapy. The orphan NR subfamily 4A (NR4A), which includes the NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor-1) genes, has been implicated in adult solid tumors and has been characterized as pro-tumorigenic mediator of cell proliferation, transformation, migration, and drug resistance. Alternatively, in leukemia, NR4A1 and NR4A3 have been described as tumor suppressors in hematologic malignancies. Members of the NR4A family are commonly overexpressed in cancer and this has …

Hexokinase Ii Localization Is Independent Of Ampk Activation In Hela Cells, Alyssa Brown

Graduate School of Biomedical Sciences Theses and Dissertations

In order for a cancer cell to thrive, it must alter its metabolism to produce the energy needed for rapid growth. Cells accomplish this by the Warburg Effect, or switching metabolism to aerobic glycolysis, where a cell can rapidly break down sugar into ATP, lactic acid and additional byproducts. Hexokinase 2, the enzyme that catalyzes the first committed step of glycolysis, may also be upregulated in cancer cells to increase glucose breakdown. Similar proteins for metabolism are found in both S. cerevisiae and mammalian cells. S. cerevisiae regulates metabolism through glucose repression, by Snf1 (mammalian homolog: AMPK) activation, which aids …

Role Of Sulfiredoxin Interacting Proteins In Lung Cancer Development, Hedy Chawsheen

Theses and Dissertations--Toxicology and Cancer Biology

Sulfiredoxin (Srx) is an antioxidant enzyme that can be induced by oxidative stress. It promotes oncogenic phenotypes of cell proliferation, colony formation, migration, and metastasis in lung, skin and colon cancers. Srx reduces the overoxidation of 2-cysteine peroxiredoxins in cells, in addition to its role of removing glutathione modification from several proteins. In this study, I explored additional physiological functions of Srx in lung cancer through studying its interacting proteins. Protein disulfide isomerase (PDI) family members, thioredoxin domain containing protein 5 (TXNDC5) and protein disulfide isomerase family A member 6 (PDIA6), were detected to interact with Srx. Therefore, I proposed …

How The Manipulation Of The Ras Homolog Enriched In Striatum Alters The Behavioral And Molecular Progression Of Huntington’S Disease, Franklin A. Lee

LSU New Orleans Theses and Dissertations

Huntington’s disease is an incurable, progressive neurological disorder characterized by loss of motor control, psychiatric dysfunction, and eventual dystonia leading to death. Despite the fact that this disorder is caused by a mutation in one single gene, there is no cure. The mutant Huntingtin (mHtt) protein is expressed ubiquitously throughout the brain but frank cell death is limited to the striatum. Recent work has suggested that Rhes, Ras homolog enriched in striatum, which is selectively expressed in the striatum, may play a role in Huntington’s disease neuropathology. In vitro studies have shown Rhes to be an E3 ligase for the …

Epacs: Epigenetic Regulators That Affect Cell Survival In Cancer., Catherine Murari

Theses & Dissertations

Cyclic adenosine monophosphate (cAMP) is a second messenger responsive to many external stimuli, playing an important role in cellular gene expression, metabolism, migration, differentiation, hypertrophy, apoptosis and secretion. All of these cellular functions are important in many diseases including cancer. Most of its effects were initially attributed to the classical protein kinase A (PKA) protein, but cellular functions such as proliferation and migration were found to be PKA independent and dependent on the newly discovered exchange proteins directly activated by cAMP (EPACs). EPACs are single polypeptides that primarily function as guanine exchange factors (GEFs) for Rap proteins that allow the …

Methylation Of Egfr By Arginine Methyltransferase Prmt1 Enhances Egfr Signaling And Cetuximab Resistance, Hsin-Wei Liao

Dissertations and Theses (Open Access)

Protein modifications of epidermal growth factor receptor (EGFR) intracellular domain are well known regulators of EGFR functions whereas those of its extracellular domain remain relatively unexplored. Here, we report that methylation at R198 and R200 of EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) upregulates its binding to EGF and subsequent receptor dimerization and signaling activation. Methylation-defective EGFR mutant reduced tumor growth in mouse orthotopic xenograft model. Importantly, increased EGFR methylation sustains its signaling activation and cell proliferation in the presence of therapeutic EGFR monoclonal antibody, cetuximab. EGFR methylation level also correlates with higher recurrence rate after cetuximab treatment …

Multilevel Deregulation Of Survival Mechanisms In Npm-Alk+ T-Cell Lymphoma, Deeksha Vishwamitra

Dissertations and Theses (Open Access)

The anaplastic lymphoma kinase (ALK) is a single chain transmembrane receptor tyrosine kinase that belongs to the insulin receptor superfamily. Other members of this superfamily include the insulin receptor (IR), type I insulin-like growth factor receptor (IGF-IR), and the leukocyte tyrosine kinase. The common structural finding among these tyrosine kinases is the YXXXYY motif present within their respective tyrosine kinase domains. Binding of its ligands causes ALK receptor homodimerization and protein kinase activation. ALK has been previously shown to play a significant role during early developmental stages. In human embryos, the expression of ALK is mainly seen in …

The Use Of Rna Interference To Mitigate Pulmonary Fibrosis In Response To Asbestos Exposure, Sarah Kinsey

Undergraduate Theses, Professional Papers, and Capstone Artifacts

The adverse health effects of exposure to asbestos are widely known and have been well documented. When a person is diagnosed with asbestosis, a chronic lung disease caused by inhaling asbestos fibers, few treatment options exist, none of which halt or reverse the progression of the disease. The rapidly growing field of gene therapy offers new avenues for potential treatments worthy of investigation. The detrimental effects of asbestos exposure are due to the physiological response of the lungs to asbestos fibers in the form of fibrosis, a result of excess extracellular collagen deposition. A protein called SPARC (Secreted Protein Acidic …

Gene Expression And Alzheimer's Disease: Evaluation Of Gene Expression Patterns In Brain And Blood For An Alzheimer's Disease Mouse Model, Amanda Hazy

Senior Honors Theses

Previous studies have established a causative role for altered gene expression in development of Alzheimer’s disease (AD). These changes can be affected by methylation and miRNA regulation. In this study, expression of miRNA known to change methylation status in AD was assessed by qPCR. Genome-wide expression changes were determined by RNA-sequencing of mRNA from hippocampus and blood of control and AD mice. The qPCR data showed significantly increased expression of Mir 17 in AD, and sequencing data revealed 230 genes in hippocampus, 58 genes in blood, and 8 overlapping genes showing significant differential expression (p value ≤ 0.05). Expression data …

Interaction Between Atm Kinase And P53 In Determining Glioma Radiosensitivity, Syed F. Ahmad

Theses and Dissertations

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Studies have shown that targeting the DNA damage response can sensitize cancer cells to DNA damaging agents. Ataxia telangiectasia mutated (ATM) is involved in signaling DNA double strand breaks. Our group has previously shown that ATM inhibitors (ATMi) sensitize GBM cells and tumors to ionizing radiation. This effect is greater when the tumor suppressor p53 is mutated.

The goals of this work include validation of a new ATM inhibitor, AZ32, and elucidation of how ATMi and p53 status interact to promote cell death after radiation. We propose that ATMi and …

Dual Pi3k/Mtor Inhibition With Bez235 Augments The Therapeutic Efficacy Of Doxorubicin In Cancer Without Influencing Cardiac Function, David E. Durrant

Theses and Dissertations

Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. …

Fty720 (Fingolimod) Provides Insight Into The Molecular Mechanisms Of Multiple Sclerosis, Madelyn Elizabeth Crawford

Pursuit - The Journal of Undergraduate Research at The University of Tennessee

Multiple sclerosis (MS) is a neurodegenerative disorder caused by a prolonged immune- mediated inflammatory response that targets myelin. Nearly all of the drugs approved for the treatment of MS are general immunosuppressants or only function in symptom management. The oral medication fingolimod, however, is reported to have direct therapeutic effects on cells of the central nervous system in addition to immunomodulatory functions. Fingolimod is known to interact with sphingosine-1-phosphate (S1P) receptors, and the most widely- accepted theory for its mechanism of action is functional antagonism of the receptor. This review examines significant neuromodulatory effects achieved by functional antagonism of the …

Characterizing The Response Of Multidrug-Resistant Klebsiella Pneumoniae Species To The Application Of A Phage Cocktail, Steven Liu

Symposium

Project Summary: The application of bacteriophages to treat bacterial infections is known as phage therapy, which takes advantage of bacteriophage’s natural ability to infect and lyse bacterial hosts. Phages have been shaped by billions of years of evolution to be highly specialized deliverers of bactericidal agents to the cytoplasm of their target bacteria. Ever since discovery of bacteriophages in 1915, phage therapy was recognized as a potentially powerful tool for eliminating bacterial infections. The effectiveness of phage therapy can be increased by creating a mixture of multiple phages to target a wider variety of bacterial strains. Furthermore, phage therapy has …