Medical Sciences Commons^™

Role Of Circular Rna Asph In Macrophage Polarization And Response In Sepsis, Tan Ze Wang

Electronic Thesis and Dissertation Repository

Circular RNAs (circRNAs), a novel non-coding RNA species generated by back-splicing, has been shown to participate in gene regulation of leukocytes. Our previous RNA sequencing results show circular RNA ASPH (circASPH) to be highly expressed in peripheral blood mononuclear cells of sepsis patients at the start of intensive care. Macrophages, as ubiquitous innate immune cells, are responsible for the recruitment of other immune cells at sepsis onset. This work investigates the role of circASPH in the regulation of macrophage polarization in sepsis. Using an in vitro THP-1 cell model, it was found that circASPH levels peaked after 24 h of …

Inflammation In The Neovaginal Microenvironment Of Transfeminine Individuals, Hannah M.J. Wilcox

Electronic Thesis and Dissertation Repository

Transfeminine individuals are assigned male at birth but do not identify as male. Some transfeminine individuals may choose to undergo the gender affirming surgery vaginoplasty to create a neovagina. There is a paucity of data on the neovaginal microenvironment to inform best gynecological practices. Vaginal and penile inflammation is modulated by local microbiota, but drivers of inflammation in the neovagina are poorly understood. The compositions of the neovaginal microbiota and immune milieu were elucidated from neovaginal swabs, using 16s rRNA gene sequencing and multiplex immunoassay, respectively. Immune data reduction and clustering was performed, and six unique immune profile types (IPTs) …

Testing A Novel Peptide-Infused Cream For Treatment Of Rheumatoid Arthritis In Dr4tg Mice, Alisha J. Moynahan

Electronic Thesis and Dissertation Repository

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes joint pain and damage. Studies have shown that inducing immune tolerance towards RA-specific proteins/peptides in RA mouse models can reduce arthritis severity and pro-inflammatory responses. The objectives of this study were to determine if a novel peptide cream treatment could modify RA-specific immune responses and reduce joint swelling in a humanized mouse model expressing the HLA-DRB1*0401 allele (known as DR4tg mice), the strongest genetic risk-factor for RA. Hyaluronan-Phosphatidylethanolamine cream infused with synthetic peptides HomoCitJED and CitJED was applied to HomoCitJED-immunized DR4tg mice before or after arthritis induction. Knee joint …

Differential Effects Of Kim-1 In Subcutaneous And Orthotopic Renca Models Of Kidney Cancer, Demitra M. Yotis Dy

Electronic Thesis and Dissertation Repository

Renal Cell Carcinoma (RCC) is the most common and fatal type of kidney cancer. Over 30% of patients that are diagnosed with RCC exhibit metastases. Almost 88% of patients with distant metastases succumb to the disease within 5 years of diagnosis. Kidney Injury Molecule-1 (KIM-1) is a cell surface glycoprotein that is not expressed in a healthy kidney but becomes highly expressed on proximal tubular epithelial cells (PTECs) following injury. Data from the Cancer Genome Atlas (TCGA) reveals that >90% of RCC tumours express KIM-1 mRNA and that higher expression levels correlate with increased overall survival rates of patients. The …

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 …

Targeting Cd5 To Enhance Immune T Cell Activation And Function In Treatment Of Solid Tumours, Faizah Alotaibi

Electronic Thesis and Dissertation Repository

CD5 is a member of scavenger receptor cysteine-rich superfamily that is expressed primarily on T cells. It can attenuate T-cell receptor signaling and impair cytotoxic T lymphocyte (CTL) activation and is a therapeutic targetable tumour antigen expressed on leukemic T and B cells. However, the potential therapeutic effect of functionally blocking CD5 to increase T cell anti-tumour activity against tumours (including solid tumours) has not been explored. CD5^- solid tumours in CD5 knockout mice display increased in anti-tumour immunity. Hence, blocking CD5 function may have a potential therapeutic effect by enhancing CTL function. Here, I assessed CD5 levels in …

Kidney Injury Molecule-1 Mediated Phagocytosis And Its Therapeutic Application In Ameliorating Renal Transplant Ischemia Reperfusion Injury, Ji Yun Lee

Electronic Thesis and Dissertation Repository

Renal transplantation is a life-saving procedure for patients with end-stage renal disease. Persistent graft inflammation and fibrosis due to injury from repeated insults - both alloantigen-dependent and -independent - lead to chronic allograft dysfunction and long-term graft loss. Ischemia-reperfusion injury (IRI) to the graft is an inescapable consequence of transplantation and can result in significant delayed graft function (DGF). Tissue damage and graft dysfunction resulting from transplant-associated IRI have been correlated with acute rejection and long-term graft loss. During IRI, dying renal proximal tubular epithelial cells (TECs) release pro-inflammatory mediators, worsening tissue damage and further potentiating injury by initiating an …

Cell-Free Dna Release During Programmed Cell Death In Kidney Ischemia Reperfusion Injury, Alexander Dionne

Electronic Thesis and Dissertation Repository

Transplantation is invariably associated with ischemia reperfusion injury (IRI) which causes organ dysfunction. IRI is also directly linked to several forms of programmed cell death including apoptosis and necroptosis, which increase kidney dysfunction, promote inflammation and may contribute to premature graft failure. The contribution of necroptosis and apoptosis following kidney IRI to cell-free DNA (cfDNA) generation and the potential of cfDNA to activate effectors such as NK cells involved in kidney IRI have not been defined. Our data indicate that necroptotic microvascular endothelial cells (MVECs) release considerably more cfDNA than apoptotic MVECs or untreated controls (p

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 …

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 …

Cell-Free Dna Release During Programmed Cell Death In Ischemia Reperfusion Injury, Alexander Dionne, Anthony M. Jevnikar, Zhu-Xu Zhang

Western Research Forum

Transplantation is invariably associated with acute allograft injury caused by ischemia reperfusion injury (IRI). This injury causes cells of the allograft to undergo various forms of programmed cell death including apoptosis and necroptosis. During programmed cell death, immunogenic molecules are released from cells, one of which is cell-free DNA (cfDNA). We hypothesize that cfDNA is released by microvascular endothelial cells (MVECs) during programmed cell death of IRI and that cfDNA acts as both a biomarker for cellular injury as well as a biologically active molecule capable of amplifying inflammation and organ injury.

Our results indicate that cfDNA is released by …

Immunological Impact Of Cli-095 On Dendritic Cell Maturation And Hypoxia-Re-Oxygenation Induced Inflammatory Injury, Hajed Obaid Alharbi

Electronic Thesis and Dissertation Repository

Immunological Impact of CLI-095 on Dendritic Cell Maturation and Hypoxia-re-oxygenation induced inflammatory injury

Introduction: Ischemia reperfusion injury (IRI) activates innate immunity through the engagement of Toll-Like Receptors (TLRs) by endogenous ligands. TLR4 expressed within the kidney is a potential mediator of innate activation and inflammation. Stimulation of TLR4 induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also to the development of acquired immunity. CLI-095, a novel synthetic small-molecule, suppresses production of multiple cytokines by inhibiting TLR4 signaling. In this study, we have determined the role of TLR4 in hypoxia and re-oxygenation …

Translational Study Of Liver Cancer And Hypertrophy: Translich, Mauro Enrique Tun Abraham

Electronic Thesis and Dissertation Repository

Abstract

Background: Associating liver partition with portal vein ligation for staged-hepatectomy (ALPPS) is a technique for inducing accelerated hypertrophy in patients with insufficient future liver remnant (FLR). It remains unknown whether this hypertrophy may lead to rapid cancer cell dissemination and/or alteration of immune cell/function reconstitution in the FLR. We aimed to determine if the rapid hypertrophy during ALPPS procedure results in more circulating tumour cell (CTCs) dissemination and whether the FLR remains immunologically competent in patients with CRLM.

Methods: In our prospective, observational, 2-arm study, we assessed the utility of CTCs as an evaluation tool for disease dissemination. Moreover, …

Synthesis, Self-Assembly, And Immunological Activity Of Α-Galactose-Functionalized Dendron–Lipid Amphiphiles, John Trant, Namrata Jain, D. M. Mazzuca, J Trevor Mcintosh, Bo Fan, S M Mansour Haeryfar, Sebastien Lecommandoux, Elizabeth Gillies

Chemistry Publications

Nanoassemblies presenting multivalent displays of biologically active carbohydrates are of significant interest for a wide array of biomedical applications ranging from drug delivery to immunotherapy. In this study, glycodendron–lipid hybrids were developed as a new and tunable class of dendritic amphiphiles. A modular synthesis was used to prepare dendron–lipid hybrids comprising distearylglycerol and 0 through 4th generation polyester dendrons with peripheral protected amines. Following deprotection of the amines, an isothiocyanate derivative of C-linked α-galactose (α-Gal) was conjugated to the dendron peripheries, affording amphiphiles with 1 to 16 α-Gal moieties. Self-assembly in …

Granulocyte Colony-Stimulating Factor: Its Role In Gut-Homing Macrophage Generation And Colitis, And Production By Probiotics, Shahab Meshkibaf

Electronic Thesis and Dissertation Repository

The pleiotropic cytokine granulocyte-colony stimulatory factor (G-CSF) is mainly required for the generation of neutrophils, but its role in macrophage generation has also been reported. In addition, G-CSF is effective for the down-regulation of inflammatory cytokines and ameliorating gut disorders, such as colitis. However, the G-CSF function in macrophage generation and gut immunity remains unclear. The first focus of this thesis was to assess the role of G-CSF in macrophage generation and its contribution to gut immunity. G-CSF was found to promote the generation of Gr-1high/F4/80+ macrophages in macrophage (M)-CSF-treated bone marrow cells, most likely through suppressing cell death. Gr-1high …

Cell Death Regulates Injury And Inflammation During Renal Allograft Transplantation, Arthur Lau

Electronic Thesis and Dissertation Repository

Renal transplantation invariably results in tissue injury resulting from ischemia reperfusion injury (IRI), inflammation, drug toxicity, and rejection. Tubular epithelial cells (TEC) comprise the majority of renal parenchyma and are susceptible to cell death and injury during diverse forms of inflammation, which has direct and indirect effects on long term allograft function. Renal TEC have the unique ability to attenuate inflammation and alloimmune injury through the expression of various mediators of cell death and inflammatory molecules. Inhibition of cell death pathways in renal allografts may influence outcomes of alloimmune responses and graft survival. In this body of investigation, alteration of …

Transcriptional Regulation Of Peptidylarginine Deiminase Type Iv: Implications For Rheumatoid Arthritis, Ali Abbas

Electronic Thesis and Dissertation Repository

High titers of anti-citrullinated protein antibodies have been detected in sera of rheumatoid arthritis (RA) patients, implicating citrullinating enzymes in the pathogenesis of RA. Peptidylarginine deiminase type IV (PAD4) is a member of the PAD family of enzymes that catalyze the post- translational modification of arginine to citrulline and has been linked with RA. However, little is known about its transcriptional regulation. Therefore, our aim was to determine how transcription of PAD4 is activated in the myeloid lineage. Using bioinformatics, a potential nuclear factor kappa B (NF-kB) binding site was identified on the PAD4 promoter. Luciferase assays were used to …

Reciprocity In Microbiome And Immune System Interactions And Its Implications In Disease And Health., Enayat Nikoopour, Bhagirath Singh

Microbiology & Immunology Publications

Adaptation of the whole microbial normal flora residing in a host to its natural habitat over an evolutionary period has resulted in peaceful coexistence with mutual benefits for both microbiota and host in steady state. This symbiotic relationship between host and microbiota has a significant impact on shaping the immune response in the host to achieve an immune tolerance to microbiota but retaining the ability to respond to invading pathogens. Perturbation of this balance by manipulation of microbial communities in the host can lead to immune dysregulation and susceptibility to diseases. By studying the host in the absence of microbiota …

The Role Of Il-22 Produced By Th17 Cells In Type 1 Diabetes, Stacey M. Bellemore

Electronic Thesis and Dissertation Repository

Interleukin-22 (IL-22) is produced by T helper 17 (Th17) cells. Th17 cells have been shown to be pathogenic in autoimmune diseases, however their role in type 1 diabetes (T1D) remains controversial. We have shown that Th17-differentiation of naïve T cells can be driven by IL-23 + IL-6 to produce large amounts of IL-22 and induce T1D. Conversely, polarizing T cells using TGF-β + IL-6 led to nonpathogenic Th17 cells that produced lower IL-22 levels. We have shown that neutralizing IFN-γ during polarization leads to a drastic increase in IL-22. We have also found IL-22-producing cells in the pancreas of diabetic …

The Role Of Pu.1 And Spi-B In B Cell Acute Lymphoblastic Leukemia, Shereen Turkistany

Electronic Thesis and Dissertation Repository

ETV6-RUNX1 is the most common chromosomal alteration in pediatric B cell acute lymphoblastic leukemia. ETV6-RUNX1 represses RUNX1 target genes. However, little is known about the target genes of ETV6-RUNX1 that are involved in promoting leukemogenesis. A recent study with two human leukemia cell lines AT-2 and REH, which express ETV6-RUNX1, suggested that SPIB was one of the top of the genes that were up regulated after knocking down the ETV6-RUNX1 fusion protein. In addition, our lab showed that deletion of PU.1 and Spi-B in B cells in mice resulted in the development of B cell acute lymphoblastic leukemia with 100% …

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 …

Regulation Of Nk Cell-Mediated Tubular Epithelial Cell Death And Kidney Ischemia-Reperfusion Injury By The Nkr-P1b Receptor And Clr-B, James Yip

Electronic Thesis and Dissertation Repository

Renal ischemia-reperfusion injury (IRI) occurs following reduced renal blood flow and is a major cause of acute injury in both native and transplanted kidneys. We have previously demonstrated that NK cells can mediate tubular cell death and kidney IRI. Natural killer receptor-protein 1B (NKR-P1B) has been shown to interact with C-type lectin-related protein B (Clr-b), resulting in the suppression of NK cell-mediated cytotoxicity.

Clr-b mRNA and protein expression in the kidney were up-regulated after renal IRI. Similar upregulation of Clr-b expression was seen in cytokine-challenged primary-cultured tubular epithelial cells (TEC). Furthermore, NK cytotoxicity assays demonstrated enhanced necrotic death in TEC …