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<p>Obesity is associated with a state of chronic, low-grade inflammation that contributes to the development of insulin resistance. Exercise is known to improve insulin resistance, and emerging evidence suggests that exercise also reduces adipose tissue inflammation. However, the relationship between exercise and inflammation has not been separated from the confounding effect of weight loss. The objectives of this study were to 1) determine whether high-intensity interval training (HIT) improves insulin sensitivity in obese mice independent of weight loss and 2) assess the effect of exercise on the relationship between adipose tissue inflammation and insulin sensitivity.</p> <p>C57BL/6 mice were assigned to one of three groups: a control, chow diet (Chow), 12 weeks of high-fat diet with no exercise (HFD Sed), or 6 weeks of high-fat diet feeding followed by an additional 6 weeks of HIT (HFD Ex). In HFD-induced obese mice, HIT had no effect on body mass, epididymal fat mass, adiposity, or adipocyte size. HIT also did not alter adipose tissue inflammation, macrophage infiltration, or adipose tissue macrophage polarization/inflammation. Nevertheless, when compared to HFD Sed mice, HIT resulted in lower fasting insulin levels and improved glucose tolerance and insulin sensitivity.</p> <p>In conclusion, these finding demonstrate that HIT improves whole-body insulin sensitivity and glucose homeostasis independent of changes in body mass or adipose tissue inflammation. The benefits of exercise in obese individuals are obvious; however, the mechanisms underlying the improvements in insulin sensitivity observed following chronic, HIT remain to be elucidated.</p> / Master of Science (MSc)

<p>GM2 gangliosidoses encompass a group of chronic neurodegenerative disorders characterized by metabolic defects in ganglioside catabolism and marked intralysosomal accumulation of GM2 in central nervous system (CNS)-resident neurons. Included in this group are Tay-Sachs and Sandhoff disease. Human cases of Tay-Sachs and Sandhoff disease present with devastating neurological deterioration; however, murine models display drastically divergent phenotypes. Tay-Sachs mice avoid pathology via a sialidase-mediated bypass of β-hexosaminidase A (HEXA) deficiency, though the precise mechanism of avoidance is not fully elucidated. The following work aimed to: i) determine if the murine sialidase-mediated bypass could be potentiated in human cells, and ii) help clarify the mechanism of disease avoidance in Tay-Sachs animals.</p> <p>Adenoviral overexpression of truncated CCAAT displacement protein (CDP^831-1505) in human Tay-Sachs neuroglia augmented neuraminidase 1/lysosomal sialidase (NEU1) protein levels, which reduced intralysosomal GM2 accumulations. Chromatin immunoprecipitation revealed binding of CDP^831-1505 to the human <em>NEU1</em> promoter in Tay-Sachs neuroglia. These results provide mechanistic and functional evidence supporting therapeutic exploitation of <em>NEU1</em> for Tay-Sachs disease.</p> <p>Comparison of immunological responses of bone marrow-derived macrophages (BMDMs) to pathogen associated molecular patterns (PAMPs) or GM2 demonstrated that Sandhoff macrophages secrete increased TNF and reduced IL-10 following lipopolysaccharide stimulation. GM2 treatment failed to stimulate an immune response. Such behaviour occurred in the absence of clearly observable intralysosomal ganglioside accumulations. Altered LAMP2 protein size, potentially due to aberrant glycosylation, is hypothesized to disrupt autophagosomal/lysosomal fusion. Subsequent autophagosomal accumulation could result in inherent macrophage hypersensitivity and immunologic irritability. Downstream interleukin-10 (IL-10)/signal transducer and activator of transcription 3 (Stat3) axis, mitogen activated protein kinase (MAPK), and glycogen synthase kinase 3-beta (GSK3β) signaling pathways were affected in Sandhoff BMDMs. These data indicate inherent differences in immunological responses of BMDMs from Sandhoff mice, presumably related to their β-hexosaminidase B (HEXB) deficiency.</p> <p>Data presented here provides evidence to suggest a paradigm shift in the neurodegenerative model of Tay-Sachs and Sandhoff Diseases towards one that places immune cells as an initiating factor for widespread neuroinflammation.</p> / Master of Science (MSc)

<p>Crohn’s Disease is a chronic inflammatory bowel disease characterized by an overzealous immune response to a microbial trigger in genetically susceptible individuals. Although this microbial trigger is unknown, <em>Escherichia coli</em> with adherent and invasive properties (Adherent-Invasive <em>Escherichia coli</em>, AIEC) is preferentially enriched in a proportion of Crohn’s Disease patients. AIEC can adhere to and invade intestinal epithelial cells and replicate intracellularly within epithelial cells and macrophages <em>in vitro</em>. One important colonization factor expressed by AIEC is the type 1 fimbrial adhesin protein FimH. FimH mediates colonization of CEABAC10 transgenic mice and can bind several host cell receptors including the macrophage receptor CD48 <em>in vitro</em> indicating a potential role for FimH in macrophage interaction. However, it was not known whether FimH contributed to phagocytosis of AIEC or colonization of wild-type mice. Here we show that FimH enhances early intracellular AIEC levels <em>in vitro</em> and colonization <em>in vivo</em>. We found that deletion of <em>fimH</em> may reduce intracellular AIEC burden at 2 hours post-infection and that this effect was modulated by bacteria opsonisation. Using a competitive index assay, we show that a Δ<em>fimH</em> mutant is unable to chronically colonize CD-1 mice at the same levels as the parental strain. Our results demonstrate that FimH is an important AIEC colonization factor and may increase interaction with macrophages. Identifying factors such as FimH which contribute to colonization and persistence will further our understanding of AIEC survival strategies within the host. Development of therapeutics targeting FimH may provide a means to reduce harmful bacteria overgrowth particularly after surgical intervention.</p> / Master of Science (MSc)