Medical Molecular Biology Commons^™

The Role Of Bip Co-Chaperone Sil1 In Marinesco-Sjögren Syndrome Pathogenesis, Viraj Paresh Ichhaporia

Theses and Dissertations (ETD)

Marinesco-Sjögren syndrome (MSS) is a rare, autosomal recessive, multisystem disorder, which is characterized by cerebellar ataxia, early-onset bilateral cataracts, and progressive myopathy amongst other symptoms. MSS has been attributed to mutations in the SIL1 gene, which encodes a nucleotide exchange factor for the endoplasmicreticulum- resident Hsp70 chaperone, BiP. To date, there are 46 MSS-associated mutations that have been reported in SIL1, which occur throughout this gene and are predicted to result in a loss of SIL1’s function. The large majority of these mutations cause deletions of large fractions of the SIL1 protein. Nine MSS-associated mutations are particularly interesting because they …

Targeting The Colchicine Binding Site On Tubulin To Overcome Multidrug Resistance And Anticancer Efficacy Of Selective Survivin Inhibitors, Kinsle E. Arnst

Theses and Dissertations (ETD)

Tubulin inhibitors are widely used as chemotherapeutic agents, and their successis attributed to their ability to target microtubule dynamics and disrupt critical cellular functions including cell signaling, motility, intracellular trafficking, and mitosis. Interference with microtubule dynamics consequently disrupts mitotic progression and ultimately leads to apoptosis, validating microtubule dynamics as an excellent target for anticancer agents. While this class of drug has proven to be effective against many cancer types, the clinical efficacy of current tubulin inhibitors is often limited by the development of multidrug resistance. The most common form of resistance to these agents arises from the overexpression of drug …

Cysteine Residues Contribute To The Dimerization And Enzymatic Activity Of Human Nuclear Dutp Nucleotidohydrolase (Ndut)., Shawna M Rotoli, Julia L Jones, Salvatore J Caradonna

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

dUTPase is an enzyme found in all organisms that have thymine as a constituent of DNA. Through evolution, humans have two major isoforms of dUTPase: a mitochondrial (mDut) and a nuclear (nDut) isoform. The nuclear isoform of dUTPase is a 164-amino-acids-long protein containing three cysteine residues. nDut's starting methionine is post-translationally cleaved, leaving four unique amino acids on its amino-terminus including one cysteine residue (C3). These are not present in the mitochondrial isoform (mDut). Using mass spectrometry analyses of recombinant dUTPase constructs, we have discovered an intermolecular disulfide bridge between cysteine-3 of each nDut monomer. We have found that these …

Editorial: Ion Channel Trafficking And Cardiac Arrhythmias, Marcel A. G. Van Der Heyden, Brian P. Delisle, Hugues Abriel

Physiology Faculty Publications

No abstract provided.

The Effect Of Wild Blueberry Bioactives On Endothelial Cell Migration And Angiogenesis: An In Vitro Mechanistic, Genomic And Proteomic Approach, Panagiotis Tsakiroglou

Electronic Theses and Dissertations

The goal of this study is to investigate the effects of wild blueberry fractions (Anthocyanins and Phenolic acids) on vascular function and physiology. More specifically the potential effects of the above fractions and their combination in physiological concentrations on endothelial cell migration, angiogenesis, gene expression and proteins synthesis of markers related to the above processes. The objectives are to study whether anthocyanins, phenolic acids and their combinations (ACNs:PAs) affect: a) cell proliferation, b) speed of endothelial cell migration, c) angiogenesis, d) gene expression of genes critical for cell migration and angiogenesis such as RAC1, RHOA, AKT1, eNOS and VEGF and …

Inhibition Of Ribosome Biogenesis Through Genetic And Chemical Approaches, Leonid Anikin

Graduate School of Biomedical Sciences Theses and Dissertations

In order to maintain the ability to generate proteins, proliferating cells must continuously generate ribosomes, designating up to 80% of their energy to ribosome biogenesis (RBG). RBG involves transcription of rDNA by RNA polymerases I (Pol I) and III (Pol III), expression of approximately 80 ribosomal proteins, and assembly of these components in a process referred to as ribosome maturation. During maturation, the Pol I transcribed 47S pre-rRNA undergoes a number of processing events, while simultaneously interacting with processing factors and ribosomal proteins that drive pre-ribosome assembly. Inhibition of RBG has become one of the pursued targets for cancer therapy …

Extrinsic And Intrinsic Factors In Liver Development, Amrita Palaria

Doctoral Dissertations

Liver is the largest internal organ of the human body. It performs a multitude of functions. Therefore, it is provided with a huge regenerative capacity however, because of the same reason it is also prone to various diseases. Hence, it is essential to understand liver development in order to understand liver regeneration and liver diseases to provide better therapeutic targets and solutions. Liver development is orchestrated by a variety of intrinsic and extrinsic factors. The major focus of this dissertation thesis is to elucidate the role of BMP signals and YY1/VEGFA regulated signals in liver development. Liver organogenesis initiates with …

Loss Of Marv1 Promotes Chop Signaling In Mouse Liver, Shad Anthony Mitchell

Graduate School of Biomedical Sciences Theses and Dissertations

Metabolic syndrome (MetS) is a term used to define a set of metabolic diseases: obesity, type 2 diabetes (T2D), hyperlipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic hepatosteatosis (NASH). Those with MetS have a higher incidence of cardiovascular disease and stroke. Current drug treatments for MetS treat the individual pathologies associated with the diseases, rather than directly targeting MetS as a whole. We hypothesize that the inhibition of a ubiquitous lipid transporter known as ARV1 can improve pathologies associated with MetS. To test this hypothesis, we utilized liver tissue from mARV1 knockout mice fed a high-fat diet and examined …

A Humanized Hypertrophic Cardiomyopathy Model To Elucidate Molecular Mechanism In Disease Pathology, Ragavi Vijayakumar, Maxine Hong

The International Student Science Fair 2018

Hypertrophic cardiomyopathy (HCM), that clinically manifests as an enlarged heart is a highly prevalent cardiac disorder with propensity towards arrhythmia-induced sudden cardiac death. The mechanism of HCM remains poorly defined, necessitating further understanding of the disease for improved therapeutic strategies. As it is challenging to obtain cardiac biopsies from human subjects, using induced pluripotent stem cells technology, we generated cardiomyocytes (CMs) in a dish from HCM patients. These HCM-CMs presented the clinical manifestation in that they were significantly larger in size in comparison to control (healthy)-CMs. Furthermore, gene expression profiling of cardiac ion channels revealed increased transcripts encoding for calcium …

Defining The Radioresponse Of Mossy Cells, Devon Ivy

Electronic Theses, Projects, and Dissertations

Clinical radiotherapy is used to treat a variety of brain tumors within the central nervous system. While effective, it can result in progressive and debilitating cognitive impairment that can diminish quality of life. These impairments have been linked to hippocampal dysfunction and corresponding deficits in spatial learning and memory. Mossy cells are a major population of excitatory neurons located within the dentate hilus and highly involved in hippocampal circuitry. They play critical roles in spatial navigation, neurogenesis, memory, and are particularly vulnerable to a variety of neurotoxic insults. However, their sensitivity to ionizing radiation has yet to be investigated in …

Till Death Do Us Part: The Marriage Of Autophagy And Apoptosis., Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Autophagy is a widely conserved catabolic process that is necessary for maintaining cellular homeostasis under normal physiological conditions and driving the cell to switch back to this status quo under times of starvation, hypoxia, and oxidative stress. The potential similarities and differences between basal autophagy and stimulus-induced autophagy are still largely unknown. Both act by clearing aberrant or unnecessary cytoplasmic material, such as misfolded proteins, supernumerary and defective organelles. The relationship between reactive oxygen species (ROS) and autophagy is complex. Cellular ROS is predominantly derived from mitochondria. Autophagy is triggered by this event, and by clearing the defective organelles effectively, …

Role Of Smarce1 And Bhlhe40 In Breast Cancer Metastasis, Aarti Sethuraman

Theses and Dissertations (ETD)

No abstract provided.

Comparison Of Serum And Cervical Cytokine Levels Throughout Pregnancy Between Preterm And Term Births, Kristin Ashford, Niraj R. Chavan, Amanda T. Wiggins, Molly Malany Sayre, Andrea Mccubbin, Agatha S. Critchfield, John O'Brien

Nursing Faculty Publications

Objective To assess differences in cytokine levels in cervicovaginal fluid (CVF) and serum across trimesters between women with preterm births (PTBs) and full-term births.

Study Design This multicenter study enrolled 302 women with a singleton gestation. CVF and serum cytokines, interleukin 1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and matrix metalloproteinase (MMP)-8, were measured. Women with at least one cytokine assessment and noted PTB status in their medical record were retained in the study (N = 272). Data were analyzed using mixed modeling (main effects of PTBs and time/trimester).

Results For the CVF …

A Lin28b Tumor-Specific Transcript In Cancer, Weijie Guo, Zhixiang Hu, Yichao Bao, Yuchen Li, Shengli Li, Qiupeng Zheng, Dongbin Lyu, Di Chen, Tao Yu, Yan Li, Xiaodong Zhu, Jie Ding, Yingjun Zhao, Xianghuo He, Shenglin Huang

Markey Cancer Center Faculty Publications

The diversity and complexity of the cancer transcriptome may contain transcripts unique to the tumor environment. Here, we report a LIN28B variant, LIN28B-TST, which is specifically expressed in hepatocellular carcinoma (HCC) and many other cancer types. Expression of LIN28B-TST is associated with significantly poor prognosis in HCC patients. LIN28B-TST initiates from a de novo alternative transcription initiation site that harbors a strong promoter regulated by NFYA but not c-Myc. Demethylation of the LIN28B-TST promoter might be a prerequisite for its transcription and transcriptional regulation. LIN28B-TST encodes a protein isoform with additional N-terminal amino acids and is critical for cancer …

Microrna 1207-3p In Prostate Cancer, Dibash Das

Dissertations, Theses, and Capstone Projects

Prostate cancer (PCa) is the most commonly diagnosed male cancer and the second leading cause of cancer-related death for men in the United States. Understanding the molecular mechanisms involved in progression from the asymptomatic androgen-dependent PCa to the lethal castration resistant prostate cancer (CRPC) is a major challenge. MicroRNAs (miRNAs), are known to be dysregulated in PCa. MicroRNA-1207-3p (miR-1207-3p) is encoded by the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of miR-1207-3p in PCa is unclear. We have discovered that miR-1207-3p is significantly underexpressed in PCa cell lines …

V-Atpase Roles In Prostate Cancer, Yamhilette Licon Munoz

Biomedical Sciences ETDs

Vacuolar ATPase (V-ATPase) is responsible for maintaining the acidic pH of the endomembrane system in eukaryotic cells. V-ATPase active transport of protons generates the differential luminal pH in lysosomes, endosomes, and the Golgi. In addition to intracellular V-ATPase, cancer cells have V-ATPase at the plasma membrane. Plasmalemmal V-ATPase acidifies the extracellular milieu and enhances cell motility and invasion, evidence that V-ATPase contributes to tumorigenic phenotypes. We studied V-ATPase cellular functions in prostate cancer (PCa), the most commonly diagnosed cancer for men in the United States. V-ATPase inhibitors decreased invasion and migration of PCa cells. In aggressive PCa cell lines, C4-2B …

The Function Of Erbin, A Scaffold Protein, As A Tumor Suppressor In Colon Cancer, Payton D. Stevens

Theses and Dissertations--Molecular and Cellular Biochemistry

Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that play important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colon cancer. Analysis of Erbin expression in patient specimens reveals that Erbin is downregulated at both mRNA and protein levels in tumor tissues. Functionally, knockdown of Erbin disrupts epithelial cell polarity and increases cell proliferation in 3D culture. In addition, silencing Erbin results in an increase in the amplitude and duration of signaling through Akt and RAS/RAF pathways. Moreover, Erbin-loss induces epithelial-mesenchymal transition (EMT), which coincides with …

Role Of Oxidized Extracellular Vesicles As Early Biomarkers And Inflammatory Mediators In Chemotherapy-Induced Normal Tissue Injury, Chontida Yarana

Theses and Dissertations--Toxicology and Cancer Biology

Significant advances in the efficacy of cancer therapy have been accompanied by an escalation of side effects that result from therapy-induced injury to normal tissues. Patients with high grade cancer or metastasis are often treated with chemotherapy, 50% of which are associated with reactive oxygen species generation and cellular oxidative stress. Heart is the normal tissue most susceptible to chemotherapy-induced oxidative stress and heart disease is the most common leading cause of death in cancer survivors. However, early and sensitive biomarkers to identify heart disease are still lacking. Extracellular vesicles (EVs) are released from cells during oxidative stress and send …

Persistent Stress-Induced Neuroplastic Changes In The Locus Coeruleus/Norepinephrine System, Olga Borodovitsyna, Neal Joshi, Daniel Chandler

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

Neural plasticity plays a critical role in mediating short- and long-term brain responses to environmental stimuli. A major effector of plasticity throughout many regions of the brain is stress. Activation of the locus coeruleus (LC) is a critical step in mediating the neuroendocrine and behavioral limbs of the stress response. During stressor exposure, activation of the hypothalamic-pituitary-adrenal axis promotes release of corticotropin-releasing factor in LC, where its signaling promotes a number of physiological and cellular changes. While the acute effects of stress on LC physiology have been described, its long-term effects are less clear. This review will describe how stress …

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

Graduate Theses, Dissertations, and Problem Reports

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 …