Digital Commons Network^™

Discovery Of Novel Mechanisms Regulating Cancer Extravasation In The Chorioallantoic Membrane Model, Yohan Kim

Electronic Thesis and Dissertation Repository

Cancer metastasis is a multistep process that begins with the invasion of tumour cells into the stroma and migration towards the blood vessels. Tumour cells that have entered the bloodstream must then survive and leave by a process known as extravasation. Finally, extravasated cells proliferate and establish the secondary site in the metastatic cascade. Although extravasation encompasses key events during cancer cell invasion to aid in the development of effective treatments, an in vivo model that rapidly, reproducibly and economically recapitulates cancer cell extravasation is needed. Therefore, the objectives of my research were to 1) establish and validate an in …

The Characterization Of The Rat Bone Sialoprotein Knockout Phenotype, Benjamin Harvey

Electronic Thesis and Dissertation Repository

Bone sialoprotein (BSP) is an extracellular phosphoprotein that has been associated with mineralizing tissues, such as the periodontium, the fibrocartilaginous enthesis, and long bone formation. In this study, we characterized the phenotype of BSP-deficient rats. Histomorphometric analysis discovered a thinning of the acellular cementum in both 20 and 50 week-old Bsp^-/- rats with no related periodontal defects and an organized periodontal ligament. Analysis of the mature quadriceps tendon (QCT) enthesis determined that BSP and osteopontin are present in the calcified fibrocartilage of wild-type rats at 14 weeks. The developing QCT enthesis of Bsp^-/- rats appears similar in mineral …

Encountering Lectins In The Recipient Mucosa: Implications Of N-Linked Glycosylation On Hiv-1 Transmission, Adam Meadows

Electronic Thesis and Dissertation Repository

Although several studies have determined key differences in envelope motifs between TF and chronic HIV-1, it is still not known what the overall glycosylation profile is that is selected for in a transmission event, as well as what contributes to this selection. Using a bottom-up approach of modifying specific viruses, determining their transmission fitness in an ex vivo tissue explant assay, and determining their glycan content, we have laid the basis for determining the overall glycan structure which is selected for in TF HIV-1. Preliminarily, we have shown that C-type lectins represent a stringent barrier to transmission and have several …

Endogenous, Controlled Expression Of Anti-Hiv-1 Broadly Neutralizing Antibody, Darshit Patel

Electronic Thesis and Dissertation Repository

Recently, researchers have identified a number of anti-HIV broadly neutralizing antibodies (bNAbs), such as VRC01 and N6, capable of targeting a broad range of HIV-1 strains. Passive immunization using these patient-derived bNAbs could provide temporary protection but are limited by the short antibody half-life. While current gene transfer technology allows sustained bNAb expression, it lacks the ability to control bNAb production in vivo resulting in possible autoimmunity. To address this issue of achieving controlled bNAb expression in vivo, we hypothesize that bNAb expression from transduced Flu-specific B cells can be activated and modulated by subsequent Flu immunizations in the …

Maternal Nicotine Exposure Induces Congenital Heart Defects In The Offspring Of Mice, Elizabeth Greco

Electronic Thesis and Dissertation Repository

Congenital heart defects are the most prevalent birth defect, and maternal cigarette smoking is a known risk factor. Nicotine replacement therapies are recommended to pregnant women who smoke to aid in smoking cessation, as this alternative is thought to be much safer compared to cigarette smoking. However, these products contain nicotine, and the safety of nicotine on the developing heart is not well known. In this thesis, a mouse model was used to test the hypothesis that maternal nicotine exposure (MNE) during pregnancy leads to congenital heart defects and coronary artery defects in the offspring of mice. MNE resulted in …

The Role Of C-Kit And Insulin Receptor Tyrosine Kinases In Beta Cell Function And Insulin Secretion, Amanda Oakie

Electronic Thesis and Dissertation Repository

The receptor tyrosine kinases (RTKs) c-Kit and insulin receptor (IR) initiate similar intracellular signalling pathways in pancreatic beta cells to regulate beta cell proliferation, survival, and insulin secretion. Mice with a c-Kit overexpression specifically in beta cells (c-KitβTg) demonstrated improved beta cell proliferation and insulin secretion compared to control mice, and islets from c-KitβTg mice also demonstrated increased IR expression. The potential interplay between c-Kit and IR and their roles during ageing and metabolic stress are not currently known. This work reports the examination of c-Kit and IR signalling using in vitro and in vivo models to determine their effects …

Mucosa-Associated Invariant T Cell Roles And Local Responses In Cell-Mediated Immunity To Influenza A Virus, Christine Marie Wardell

Electronic Thesis and Dissertation Repository

Mucosa-associated invariant T (MAIT) cells are innate-like T cells that are activated by microbial vitamin B metabolites and/or cytokine stimulation to produce pro-inflammatory cytokines and cytotoxic granules. Influenza A viruses (IAVs) activate MAIT cells in a by-stander manner, and their abundance negatively correlates with infection-induced morbidity and mortality. However, how MAIT cells directly contribute to anti-viral immunity is ill-defined. I hypothesized that MAIT cells’ presence in mice enhances antigen-specific CD8⁺ T cell responses. I observed a trend that MAIT cell-deficient mice generally developed smaller populations of antigen-specific CD8⁺ T cells following IAV exposure than mice abundant in MAIT …

A Ph-Sensitive Delivery System For The Prevention Of Dental Caries Using Salivary Proteins, Yi Zhu

Electronic Thesis and Dissertation Repository

Dental caries remains one of the most common chronic diseases worldwide. Salivary proteins such as histatins have demonstrated biological functions directly related to tooth homeostasis and prevention of dental caries. However, histatins are susceptible to the high proteolytic activities in the oral environment. Therefore, pH-sensitive chitosan nanoparticles (CNs) have been proposed as potential carriers to target major oral diseases that occur under acidic conditions (e.g. dental caries and dental erosion). Four different types of chitosan polymers were investigated and the optimized CNs successfully loaded histatin 3 and released it selectively under acidic conditions. Through loading the survival time of histatin …

Hyperactive Torc1 Sensitizes Yeast Cells To Endoplasmic Reticulum Stress By Compromising Cell Wall Integrity, Khadija Ahmed

Electronic Thesis and Dissertation Repository

The disruption of protein folding homeostasis in the endoplasmic reticulum (ER) results in an accumulation of toxic misfolded proteins and activates a network of signaling events collectively known as the unfolded protein response (UPR). While UPR activation upon ER stress is well characterized, how other signaling pathways integrate into the ER proteostasis network is unclear. Here, I sought to investigate how the target of rapamycin complex 1 (TORC1) signaling cascade acts in parallel with the UPR to regulate ER stress sensitivity. Using S. cerevisiae, I found that TORC1 signaling is attenuated during ER stress and constitutive activation of TORC1 …

Hiv-1 Group M Subtype Fitness, Disease Progression, And Entry Efficiency, Colin M. Venner

Electronic Thesis and Dissertation Repository

Human immunodeficiency virus type 1 (HIV-1) emerged in the human population shortly after the turn of the 19th century. Distribution of HIV-1 across the globe over the past 30–35 years can be traced to founder events with primordial HIV strains from sub-Saharan Africa. Even considering the burden of HIV in Africa, our knowledge of HIV-1 disease is still largely limited to subtype B HIV-1, a strain responsible for 3 million infections in North America and Europe as compared to the 33 million that are infected with HIV-1 subtypes A, C, D, and circulating and unique recombinant forms.

This dissertation analyzes …

Mass Spectrometry-Based Proteomics Analysis Of Bioactive Proteins In Emd That Modulate Adhesion Of Gingival Fibroblast To Improve Bio-Integration Of Dental Implants, David Zuanazzi Machado Jr

Electronic Thesis and Dissertation Repository

Titanium implants are used in dental practice to replace damaged or lost teeth. The implant needs to integrate with the surrounding gingiva to protect it against bacterial invasion that leads to implant loss. The biointegration is dependent on the implant surface that interacts with proteins from biological fluids to modulate tissues response. Tailoring the surface with specific proteins from the enamel matrix derivative (EMD) would be beneficial to improve the implant-gingiva interface since EMD can affect various cells including gingival fibroblasts. A surface-affinity approach using three different titanium surfaces and saliva was utilized as a model in combination with tandem …