Medical Molecular Biology Commons^™

Lncrna Impact On Regorafenib Resistance In Colorectal Cancer, Ricardo Pequeno Bracho, Kyle Doxtater, Dennis Kwabiah, Yamile Abuchard Anaya, Sophia Leslie, Mohammad Shabir Hussain, Manish Tripathi

Research Symposium

Cancer metastasis is one of the deadliest aspects of the disease, with about 90% of all cancer-related deaths due to its development at different sites within the body. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States, with 40-50% of all patients developing metastasis at some point during their fight with the disease. With the approval of Regorafenib for treating metastatic colorectal cancer, steps have been taken to combat metastasis in colorectal cancer. A vital aspect of the development of metastasis is the development of resistance to first-line chemotherapy. Regorafenib is an oral small-molecule …

Functional Impact Of Ethyl-Β-D-Glucuronide On Mycobacterium Tuberculosis Stimulated Lung Macrophages, Charles Inaku

Biotechnology Theses

Chronic alcohol abuse has been shown to alter immune defense mechanisms in humans and mice which makes the host susceptible to infections, including Mycobacterium tuberculosis (Mtb) infection. However, limited information is available on the mechanisms involved in alcohol-mediated host immune system dysfunction.

In this study, we determined the effects of ethyl-β-d-glucuronide (EtG), an alcohol-derived metabolite, on immune response of mice lung macrophages. We measured cytokine and chemokine production by gamma-irradiated mtb (γ-mtb) stimulated mice lung macrophages in the presence or absence of EtG. We also determined the effect of EtG on the metabolic state of γ-mtb stimulated mice lung macrophages. …

Investigating The Pi3k/Akt/Atm Pathway, Telomeric Dna Damage, T Cell Death, And Crispr/Cas9-Mediated Gene Editing During Acute And Chronic Hiv Infection, Sushant Khanal

Electronic Theses and Dissertations

Human Immunodeficiency Virus (HIV) infection initiates major metabolic and cell- survival complications. Anti-retroviral therapy (ART) is the current approach to suppress active HIV replication to a level of undetected viral load, but it is not a curative approach. Newer and sophisticated gene editing technologies could indeed be a potent antiviral therapy to achieve a clinical sterilization/cure of HIV infection. Chronic HIV patients, even under a successful ART regimen, exhibit a low-grade inflammation, immune senescence, premature aging, telomeric DNA attrition, T cell apoptosis, and cellular homeostasis. In this dissertation, we investigated CD4 T cell homeostasis, degree of T cell apoptosis, an …

Attenuation Of Relapsing Fever Neuroborreliosis In Mice By Il-17a Blockade, Meihui Cheng, Jingwen Xu, Kaiyun Ding, Jing Zhang, Wei Lu, Jiansheng Liu, Jiahong Gao, Kishore R Alugupalli, Hongqi Liu

Department of Microbiology and Immunology Faculty Papers

Relapsing fever due to Borrelia hermsiiis characterized by recurrent bacteremia episodes. However, infection of B. hermsii, if not treated early, can spread to various organs including the central nervous system (CNS). CNS disease manifestations are commonly referred to as relapsing fever neuroborreliosis (RFNB). In the mouse model of B. hermsiiinfection, we have previously shown that the development of RFNB requires innate immune cells as well as T cells. Here, we found that prior to the onset of RFNB, an increase in the systemic proinflammatory cytokine response followed by sustained levels of IP-10 concurrent with the CNS disease phase. RNA sequencing …

Genomic Features Underlie The Co-Option Of Sva Transposons As Cis-Regulatory Elements In Human Pluripotent Stem Cells, Samantha M Barnada, Andrew Isopi, Daniela Tejada-Martinez, Clément Goubert, Sruti Patoori, Luca Pagliaroli, Mason Tracewell, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication …

Molecular Pathogenesis Of A Novel Subgroup Of Peripheral T-Cell Lymphomas, Jiayu Yu

Theses & Dissertations

Peripheral T-cell Lymphoma (PTCL) consists of numerous distinct disease entities. With the current diagnostic criteria over a third of the cases cannot be further classified and are called "not otherwise specified" (PTCL-NOS). Using gene expression profiling (GEP) of tumors, we identified two novels PTCL-NOS molecular subgroups either characterized by high expression of GATA3 (33%), which is associated with Th2 cell differentiation, or high expression of TBX21 (49%) which regulates Th1 cell maturation. Therefore, stratifying patients for diagnosis and identifying the underlying genetic basis to improve clinical therapy becomes critical to prognosis.

First, we performed DNA copy number analysis by using …

Candida Cell-Surface-Specific Monoclonal Antibodies Protect Mice Against Candida Auris Invasive Infection, Jonothan Rosario-Colon, Karen Eberle, Abby Adams, Evan Courville, Hong Xin

School of Graduate Studies Faculty Publications

Candida auris is a multidrug-resistant fungal pathogen that can cause disseminated bloodstream infections with up to 60% mortality in susceptible populations. Of the three major classes of antifungal drugs, most C. auris isolates show high resistance to azoles and polyenes, with some clinical isolates showing resistance to all three drug classes. We reported in this study a novel approach to treating C. auris disseminated infections through passive transfer of monoclonal antibodies (mAbs) targeting cell surface antigens with high homology in medically important Candida species. Using an established A/J mouse model of disseminated infection that mimics human candidiasis, we showed that …

Hiv-1 Drug Resistance To Integrase Strand Transfer Inhibitors In Hiv-1 Non-B Subtypes, Emmanuel Ndashimye

Electronic Thesis and Dissertation Repository

Human immunodeficiency syndrome (HIV-1) has infected over 75 million people and over 35 million have succumbed to virus related illnesses. Despite access to a variety of antiretroviral therapy (ART) options, ART programs have been disproportionally spread in the world with low-and middle-income countries (LMICs) facing challenges to access the most potent ART options. With less potent ART remaining in use in LMICs, HIV-1 drug resistance (HIVDR) presents a growing challenge in LMICs. Since approval of the first-generation integrase strand transfer inhibitor (INSTIs), Raltegravir (RAL) in 2007, INSTIs remain the best choice as a backbone of ART. Access to second generation …

A High-Throughput Approach To Characterizing Arv1 On The Regulation Of Lipid Homeostasis Uncovers A Novel Interaction With Epidermal Growth Factor Receptor, Nicholas Anthony Wachowski

Graduate School of Biomedical Sciences Theses and Dissertations

Acyl-CoA cholesterol acyl transferase related enzyme-2 required for viability 1 (ARV1) was first recognized in Saccharomyces cerevisiae in a study done in 2000 by Tinkelenberg et al. In yeast, the deletion of ARV1 results in numerous defects including abnormal sterol trafficking [1], the reduction of sphingolipid metabolism [2], synthesis of glycosylphosphatidylinositol (GPI) anchor [3], ER stress [4], and hypersensitivity of fatty acids leading to lipoapoptosis [5]. Arv1 germline deletion in mice displayed a lean phenotype with increased energy [6]. In humans, ARV1 mutations lead to epileptic encephalopathy [7].

Non-alcoholic fatty liver disease (NAFLD) consists of simple steatosis to non-alcoholic steatohepatitis …

Therapeutic Potential Of Trp Channels In The Targeting Of Rheumatoid Arthritis Synovial Fibroblasts, Brittany Isabella Schwam

Theses and Dissertations (ETD)

Rheumatoid arthritis is a chronic inflammatory disease primarily affecting the synovium, articular cartilage, and bone within a joint, but it is a unique form of arthritis wherein effects are systemic. The cause of this autoimmune disease remains unknown, but there are many environmental and genetic factors that play into susceptibility. Research is still far from drug-free remission despite great advancements over the past few decades. The majority of therapies developed rely on immunosuppressant or immunomodulator molecules and come with risk of infection, high costs, and toxic, uncontrolled side effects. Those diagnosed maintain a significant unmet need for targeted therapies.

There …

It's A Hard Nacht Life: Understanding How Nlrp12 Ticks, Abbigale Julia Brown

MSU Graduate Theses

The protein NOD- like receptor pyrin domain containing 12 (NLRP12) comes from a family of protein receptors with a wide range of functions including fertility as well as anti-inflammatory properties. The biological role of NLRP12 is poorly understood: research on the mechanisms behind its function and/or activation remains contradictory between different cell models. Current research suggests its involvement in a multi-protein complex named the inflammasome. The alternative hypothesis that has also been proposed is that NLRP12 is not a part of the inflammasome, rather it negatively regulates a transcription factor known as NF-��B down stream of Toll-like receptors. NLRP12 is …

Virally Packaged Rna In Virus-Like Particle Vaccines Enhances Antigenicity And Augments Latency Reversal Of Hiv-1, Chanuka Wijewardhana

Electronic Thesis and Dissertation Repository

Introduction:

Since Human Immunodeficiency Virus (HIV)-1 was determined to be the etiological agent behind acquired immunodeficiency syndrome (AIDS) in 1983, numerous attempts at a cure have been made; however, none have been effective. One of the primary roadblocks in achieving a cure is a transcriptionally-silent latent reservoir of memory CD4+ T cells harboring HIV provirus. Combined antiretroviral therapy (cART) inhibits actively replicating virus by interfering with various stages of the replication cycle. Therefore, non-replicative viruses–like the proviruses found in latently infected cells–are hidden from the actions of continued antiretroviral therapy. As a result, cART discontinuation or treatment holidays can result …

Natural Autoantibodies: Origin, Function And Utility For Diagnosis Of Disease, Abhirup Sarkar

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies (aAbs) by the simplest definitions have been described as antibodies against self-antigens and were exclusively associated with autoimmune diseases. Eventually, studies demonstrated that they are abundant in the blood of all human sera, regardless of age, gender, or the presence or absence of disease, and were thus named as ‘natural autoantibodies’. The underlying reason for their ubiquity has remained elusive, but we have hypothesized that they are responsible for clearing blood-borne cell and tissue debris generated under conditions of health and disease. To test this, we chose to use two widely different disease model systems, namely neurodegenerative diseases and …

Modulation Of Inflammation Driven Wound Healing After Glaucoma Surgery, James J. Armstrong

Electronic Thesis and Dissertation Repository

Dysregulated wound healing contributes to most currently unanswered ophthalmological morbidity. Opacification and structure altering contractures compromise the delicate ocular anatomy upon which ocular function and healthy vision are reliant. Glaucoma filtration surgery, corneal stromal injury, proliferative vitreoretinopathy and age-related macular degeneration are major contributors to ocular morbidity – all with myofibroblast transdifferentiation and pathognomonic scarring activity at their core.

This thesis aims to revaluate the means by which dysregulated ocular wound healing is combated with evidence describing a novel strategy to mitigate its effects. A translational approach was used. An initial retrospective analysis of over ten thousand glaucoma surgeries found …

Transcriptional Regulation Of Nlrc4 Inflammasome By Irf8, Ein Lee

Theses and Dissertations (ETD)

The NLRC4 inflammasome is a crucial part of the innate immune response against bacterial infections. We found that NLRC4 inflammasome activation in bone marrow-derived macrophages (BMDMs) is greatly dependent on interferon regulatory factor 8 (IRF8). NLRC4-mediated caspase-1 activation and subsequent production of the inflammasome-dependent cytokines IL-1β and IL-18 and cell death were impaired in IRF8-deficient cells. IRF8 mediated the transcription of genes encoding NAIPs, the receptors for NLRC4 inflammasome, which recognize bacterial flagellin and type III secretion system (T3SS) proteins. IRF8 was critical for host survival following infection with Salmonella Typhimurium or Burkholderia thailandensis. Furthermore, mice deficient in IRF8 were …

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 …

Complete Genome Sequences Of Three Staphylococcus Pseudintermedius Strains Isolated From Botswana, Mohamed Adel Salaheldin Abouelkhair, Stephen A. Kania, David A. Bemis, Matthew C. Riley, Riley Thompson

Faculty Publications and Other Works -- Biomedical and Diagnostic Sciences

We report here the first whole-genome sequences for 3 strains of Staphylococcus pseudintermedius (112N, 113N, and 114N) isolated in Africa. Samples of this opportunistic pathogen were collected from nasal swabs obtained from healthy carrier dogs in Botswana. The sequence information will facilitate spatial phylogenetic comparisons of staphylococcal species and other bacteria at the genome level.

Wnt Secretion Proteins Modulate Rankl-Induced Expression Of Aire In Thymic Epithelial Cells, Daniel Pollack

Dissertations and Theses

Thymic epithelial cells (TEC) are essential for a proper adaptive immune response by regulating thymocyte development and establishing central tolerance. In the thymus, TECs differentially express Wnt proteins, which activate canonical and non-canonical Wnt signaling pathways. Wnt signaling is thought to regulate cell survival, proliferation, and development although the direct molecular mechanisms in TECs have yet to be elucidated. The inducible inhibition of canonical Wnt signaling with Dkk1 leads to a rapid loss of TEC progenitors as well as a decline in mature Aire-expressing mTECs. Therefore, we explore the role of Wnt ligands potentially responsible for stimulating and/or regulating Wnt …

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 …

The 11s Proteasomal Activator Regγ Impacts Polyglutamine-Expanded Androgen Receptor Aggregation And Motor Neuron Viability Through Distinct Mechanisms., Jill M. Yersak, Heather L. Montie, Erica S. Chevalier-Larsen, Yuhong Liu, Lan Huang, Martin Rechsteiner, Diane E. Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Spinal and bulbar muscular atrophy (SBMA) is caused by expression of a polyglutamine (polyQ)-expanded androgen receptor (AR). The inefficient nuclear proteasomal degradation of the mutant AR results in the formation of nuclear inclusions containing amino-terminal fragments of the mutant AR. PA28γ (also referred to as REGγ) is a nuclear 11S-proteasomal activator with limited proteasome activation capabilities compared to its cytoplasmic 11S (PA28α, PA28β) counterparts. To clarify the role of REGγ in polyQ-expanded AR metabolism, we carried out genetic and biochemical studies in cell models of SBMA. Overexpression of REGγ in a PC12 cell model of SBMA increased polyQ-expanded AR aggregation …

Porphyromonas Gingivalis Gingipains Induce A Pro-Inflammatory Extracellular Microenvironment : The Role Of Par-2 And Fibronectin., Jeffrey S. Marschall

Electronic Theses and Dissertations

Periodontitis is a chronic inflammatory disease that is characterized by severe tissue destruction of the gingiva and other tooth supporting structures; if left untreated, tooth loss and disintegration of the alveolar bone occurs. This chronic inflammatory state has been linked to other systemic diseases such as cardiovascular disease, diabetes, rheumatoid arthritis, and Alzheimer’s disease. Porphyromonas gingivalis is the major pathogenic microbe in periodontitis. The main virulence factors of P. gingivalis are the Arg-aa and Lys-aa gingipains, which are proteolytic enzymes implicated in a plethora of activities that allow P. gingivalis to subvert the human immune system in the oral cavity …

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 …

Novel Therapeutic Approaches For Ischemic Heart And Brain Injury: Modulation Of Toll-Like Receptor-Mediated Signaling Pathways And Pi3k/Akt Signaling, Chen Lu

Electronic Theses and Dissertations

Innate immune and inflammatory responses contribute to myocardial and cerebral ischemia/reperfusion (I/R) injury. Toll-like receptors (TLRs) play a critical role in the induction of innate immune and inflammatory responses via activation of nuclear factor kappa B (NF-κB). We have shown that activation of NF-κB contributes to myocardial and cerebral I/R injury. Indeed, inhibition of TLR4-mediated NF-κB activation significantly decreased myocardial and cerebral I/R injury via activation of PI3K/Akt signaling. PI3K/Akt signaling is an important pathway in regulating cellular survival and inflammatory responses. Therefore, an important question is how to differentially modulate PI3K/Akt signaling and TLR/NF-κB-mediated signaling pathway during I/R injury? …

Analysis Of The Role Of Astrocyte Elevated Gene-1 In Normal Liver Physiology And In The Onset And Progression Of Hepatocellular Carcinoma, Chadia L. Robertson

Theses and Dissertations

First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction …

Systematic Assessment Of The Contribution Of Superantigens To Nasopharyngeal Colonization In A Mouse Model Of Streptococcal Infection, Katherine J. Kasper

Electronic Thesis and Dissertation Repository

Streptococcus pyogenes is adapted for persistence in humans. It typically colonizes the tonsils and skin, and humans are the only known reservoir. S. pyogenes can cause a wide range of mild to serious infections. Most streptococci-related deaths are due to complications of rheumatic fever and invasive infections. S. pyogenes produces virulence factors that contribute to the pathogen’s ability to colonize and cause disease, including streptococcal superantigens (SAgs), also known as streptococcal pyrogenic exotoxins (Spes). SAgs function by cross-linking T cells and antigen presenting cells (APC) which may cause a massive inflammatory response, and as such have been found to contribute …

A Mathematical Model For Dengue Fever In A Virgin Environment, Jason K. Bowman

Senior Honors Projects

Dengue is a mosquito-borne viral infection found in tropical and subtropical regions around the world. The disease was named in 1779 and the first recorded epidemic of it occurred simultaneously on three continents within the following decade. Dengue is characterized by flu-like symptoms and, while its symptoms are generally reported as quite unpleasant, is rarely fatal. However, in some cases patients can contract a more serious form of the disease, known as Dengue Hemorrhagic Fever, which is far more dangerous. The World Health Organization estimates that today over 2.5 billion people are at risk for Dengue (over 40% of the …

The Molecular Basis Of Fitness And Transmissibility Of Neuraminidase Inhibitor Resistant Influenza A Viruses, Susu Duan

Theses and Dissertations (ETD)

Neuraminidase (NA) inhibitors including oral oseltamivir and inhaled zanamivir are among the first line of defense against influenza virus infection. Development of resistance to NA inhibitors is a huge drawback for limited options for the control of influenza. During the first decade of NA inhibitor use, the detection rates of resistance to both NA inhibitors had remained low in circulating influenza viruses. However, the 2008~2009 season was marked by a radical increase of prevalence of oseltamvir resistance from <1% to >90% in worldwide surveillance in less than a year. The resistance was solely linked to NA H275Y variants of seasonal H1N1 viruses, …

Hp Turns 17: T Helper 17 Cell Response During Hypersensitivity Pneumonitis (Hp) And Factors Controlling It, Hossam Abdelsamed

Theses and Dissertations (ETD)

Hypersensitivity Pneumonitis (HP) is an interstitial lung disease caused by repeated inhalation of a wide range of environmental antigens. It is characterized by alveolitis, granuloma formation, and fibrosis. Since HP is a T cell-mediated disease, it is important to determine the type of T cell response associated with granuloma formation and the factors that control this response. We hypothesized that HP is associated with a predominant Th17 cell response where both T-bet and TLRs 2 and 9 are controlling T cell response during HP. The results demonstrated a predominant Th17 response associated with granuloma formation in the lungs of C57BL/6J …

Signaling Mechanisms Involved In The Generation Of Human Peripheral Itregs, Mary Catherine Reneer

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Maintaining balance in the human immune system is critical for the body’s ability to discriminate between foreign and self-antigens. This balance is achieved, in part, by a subpopulation of T cells known as induced regulatory T cells (iTregs). Dysregulation of this population may contribute to the onset and progression of cancer, chronic inflammation and autoimmune diseases. Therefore, manipulation of iTreg development holds promising therapeutic potential; however, studying this vital population has proven difficult due to low numbers, heterogeneous cell populations, substantial phenotypic differences between mouse and human cells, and the high plasticity seen in iTregs. These current limitations have prevented …

Identification Of A Second Mimicry Epitope From Acanthamoeba Castellanii That Induces Cns Autoimmunity By Generating Cross-Reactive T Cells For Mbp 89–101 In Sjl Mice, Chandirasegaran Massilamany, Oluwatoyin A. Asojo, Arunakumar Gangaplara, David J. Steffen, Jay Reddy

Jay Reddy Publications

We had previously reported that Acanthamoeba castellanii (ACA) contains a mimicry epitope for proteolipid protein 139–151 capable of inducing central nervous system (CNS) autoimmunity in SJL/J mice. We now present evidence that ACA also contains a mimicry epitope for myelin basic protein (MBP) 89–101, a derivative from amoebic nicotinamide adenine dinucleotide dehydrogenase subunit 2 (NAD). The epitope, NAD 108–120, contains a discontinuous stretch of six amino acids in the core region (VVFFKNIILIGFL) sharing 46% identity with MBP 89–101 (VHFFKNIVTPRTP; identical residues are underlined). SJL mice immunized with NAD 108–120 develop encephalomyelitis similar to the disease induced by the cognate peptide. …