Medicine and Health Sciences Commons^™

The Role Of Reactive Oxygen Species In The Accumulation Of Driver Mutations In B Cell Acute Lymphoblastic Leukemia, Mia P. Sams

Electronic Thesis and Dissertation Repository

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with recurrent mutations and high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine was tested for its ability to prolong lifespan of a mouse model of B-ALL and reduce frequency of mutations. Mice treated with 1g/L of N-acetylcysteine in drinking water were found to have delayed onset of B-ALL at 11 weeks of age and changes in gene expression relating to B cell development, calcium-apoptosis signaling, and pathways in cancer, although no differences in lifespan were observed. Tumours from treated …

Connexin 43 Contributes To Phenotypic Variability Of The Mouse Skull, Elizabeth Jewlal

Electronic Thesis and Dissertation Repository

The purpose of this study was to determine whether connexin 43 (Cx43) contributes to craniofacial phenotypic variability. Skull shape and variation were compared within and among two heterozygous mutant mouse models (G60S/+ and I130T/+) that exhibit different levels of Cx43 channel function when compared to their wildtype counterparts (~80% and ~50% reduction in function, respectively). Results indicated mutants have significant differences in skull shape compared to wildtype littermates. Similar patterns of shape difference were found in both mutants. Increased skull shape variation and a disruption in the covariation of skull structures were observed in G60S/+ mutants only. These results show …

Free Fatty Acid Treatment Alters Autophagy During Mouse Preimplantation Embryo Development, Zuleika C. L. Leung

Electronic Thesis and Dissertation Repository

Obesity-induced hyperlipidemia is one of the main factors for female infertility. Hyperlipidemia, specifically with high levels of palmitic acid (PA) and oleic acid (OA), interferes with preimplantation development. Autophagy is essential in early embryo development but, it is unknown whether hyperlipidemia affects autophagic mechanisms in preimplantation embryos. It was hypothesized that PA will alter autophagy in preimplantation mouse embryos and that the subsequent effects will be reversed by OA. PA impaired blastocyst development by arresting embryos at the 8-cell stage. PA also elevated early embryo autophagy by increasing autophagosome formation, decreasing maturation, and disrupting degradation. Co-treatment with OA showed developmental …

Maternal Lifelong Western Diet Consumption Impacts Placental And Brain Development In The Term Guinea Pig Fetus, Carlene H. Cihosky

Electronic Thesis and Dissertation Repository

Both metabolic and cognitive dysfunction can originate from fetal reprogramming precipitating from adverse conditions experienced in utero. Of note is the western diet (WD), which is associated with maternal energy imbalances that may hinder fetal development through altered placental function. Brain-derived neurotrophic factor (BDNF), a growth factor that supports the placenta and developing brain, is responsive to such energy imbalances. This study sought to investigate the impact of lifelong maternal WD consumption on fetoplacental development, focusing on relations between placental changes, and fetal growth and neurodevelopment in a guinea pig model. Maternal WD consumption resulting in a lean metabolically …

The Effects Of Maternal Delta-9-Tetrahydrocannabinol And Cannabidiol Exposure On Fetal Heart Development In Mice, Gregory Robinson

Electronic Thesis and Dissertation Repository

Up to 22.6% of pregnant women consume cannabis during pregnancy despite the uncertainty of teratogenicity of the main ingredients in cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). This study tested the hypothesis that gestational THC and CBD exposure leads to heart abnormalities. Daily, oral THC exposure induced heart abnormalities in 68% of offspring with three main phenotypes including thickened semilunar valves, ventricular myocardial hypertrophy and hypoplastic coronary arteries in fetuses, and postnatal cardiac dysfunction. Altered gene expression of key cardiogenic regulators, increased proliferation, and reduced epicardial epithelial-to-mesenchymal-transition were demonstrated implicating potential mechanisms responsible for these abnormalities. Also, maternal CBD exposure resulted …

Pregestational Diabetes Induced Congenital Heart Defects And Coronary Artery Malformations; Mechanisms And Preventative Therapies, Anish Engineer

Electronic Thesis and Dissertation Repository

Congenital heart defects (CHDs) arise from perturbations in complex molecular and cellular processes underlying normal embryonic heart development. CHDs are the most common congenital malformation, occurring in 1 to 5% of live births, and are the leading cause of pediatric mortality. Adverse genetic and environmental factors can impede normal cardiogenesis and increase the likelihood of CHDs. Pregestational maternal diabetes increases the risk of CHDs in children by more than four-fold. As the prevalence of diabetes rapidly rises among women of childbearing age, there is a need to investigate the mechanisms and potential preventative strategies for these defects. The aim of …

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 …

Effects Of Maternal Protein Restriction On The Pulmonary Surfactant System During The Early Life And Adulthood, Reza Khazaee

Electronic Thesis and Dissertation Repository

Fetal growth restriction (FGR) is defined by low birth weight and contributes to a variety of adult-onset diseases with different severities between males and females. However, the effects of FGR on the pulmonary surfactant are not fully elucidated. In this thesis, first, we investigated the FGR effects on the lung function and the surfactant system at the early postnatal life. It was hypothesized that FGR contributes to alterations of lung mechanics and the surfactant system during the neonatal period. Second, we assessed the FGR effects on the surfactant system in response to sepsis in adulthood. It was hypothesized that FGR …

Examining The Tissue-Level And Gross Phenotypic Effects Of The Connexin43i130t/+ Mutation On The Developing Mouse Skull, Sommer G.E. Jarvis

Electronic Thesis and Dissertation Repository

The purpose of this study was to investigate the effects of reduced Connexin43 function on the developing skull phenotype, osteoblast and chondrocyte proliferation and differentiation, and to determine if a correlation exists between cell processes and gross morphology. Using the Cx43^I130T/+mouse model, skull shape was analyzed using geometric morphometrics and cell proliferation and differentiation were assessed using immunohistochemistry at late embryonic and early post-natal stages. The largest shape changes between Cx43^I130T/+ and wildtype mice were observed in the cranial base and facial skeleton. Changes infacial morphology correspond to reduced osteoblast differentiation. However, no changes in chondrocyte proliferation …

Contribution Of Activating Transcription Factor 3 To Development Of Acinar-To-Ductal Cell Metaplasia, Jelena Toma

Electronic Thesis and Dissertation Repository

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America. The highest risk factor for PDAC is recurrent pancreatitis. While the link between PDAC and pancreatitis is unknown, de-differentiation of acinar cells is common to both diseases. Our lab has shown that Activating Transcription Factor 3 (ATF3), a factor upregulated during pancreatic injury, contributes to the development of acinar-to-ductal cell metaplasia (ADM), a precursor phenotype of PDAC. The goal of this study was to identify how ATF3 contributes to ADM. I hypothesize that ATF3 regulates acinar gene expression promoting ADM. We observed decreased ADM development …

Panx1 And Panx3 Regulate Adipocyte Development And Fat Accumulation In Vivo, Vanessa R. Lee

Electronic Thesis and Dissertation Repository

The obesity epidemic is a growing concern due to its various comorbidities and associated risk factors. Pannexins 1 and 3 (Panx1 and Panx3), are members of a family of channel-forming glycoproteins that have been reported to be important in paracrine signaling and development. Panx1 and Panx3 are homologous and are regulated in many different cell types, mediating cell proliferation and differentiation. We have shown that Panx1 and Panx3 are expressed in adipocytes and adipose-derived stromal cells (ASCs) throughout the process of differentiation. Mice globally lacking Panx1 (Panx1 KO) have significantly greater total fat mass compared to wildtype (WT) mice under …

The Role Of Bone Sialoprotein In Periodontal Tissue Development And Bone Repair, Yohannes Soenjaya

Electronic Thesis and Dissertation Repository

Bone development and repair involve complex processes that include interaction between cells and their surrounding matrix. In the body, bone sialoprotein (BSP) expression is up-regulated at the onset of mineralization. BSP is a multifunctional acidic phosphoprotein with collagen-binding, hydroxyapatite nucleating, and integrin recognition (RGD sequence, which is important for cell-attachment and signaling) regions. Mice lacking BSP expression (Bsp^-/-), exhibit a bone phenotype with reductions in bone mineral density, bone length, osteoclast activation, and impaired bone healing. This thesis examined the role of BSP in tooth development and also its potential use as a therapeutic reagent for bone …

Characterization Of The Nicotine-Induced Endoplasmic Reticulum Stress Response In The Rat Placenta In Vivo And In Vitro, Michael Ka Chun Wong

Electronic Thesis and Dissertation Repository

Nicotine exposure during pregnancy leads to adverse health outcomes, including compromised placental development. Although the molecular mechanisms remain elusive, recent studies identified that endoplasmic reticulum (ER) stress may underlie poor placentation. Therefore, we were interested in investigating the effects of nicotine exposure on the ER stress response in the placenta. A well-established maternal nicotine exposure rat model and Rcho-1 trophoblast giant cell model were utilized to address the research questions. Maternal nicotine exposure in vivo led to elevated ER stress in association with impaired disulfide bond formation and hypoxia. Nicotine exposure in vitro further differentiated that ER stress may be …

Investigation Of Pancreatic Β-Cell Insulin Receptor Regulation Of Β-Cell Growth, Function, And Survival Via A Temporal Conditional Knockout, Liangyi Zhou

Electronic Thesis and Dissertation Repository

The expression of insulin receptor (IR) in β-cells suggests an autocrine role for insulin signalling in β-cell function and regulation. Studies have demonstrated that β-cell Ir knockout (βIrKO) mice develop age-dependent glucose intolerance. We investigated the temporal role of β-cell IR signaling in pre- and postnatal islet development and function, and under high-fat diet stress, using a tamoxifen-inducible Cre-recombinase Ir knockout mouse model.

Prenatal βIrKO mice exhibited increased mean islet area, β-cell area, and islet area percentage. Additionally, there was upregulation of insulin-like growth factor-2 levels, increased Akt activity, and increased proliferation in islets. Postnatally-induced βIrKO mice did not exhibit …

The Ctcf Chromatin Organizer Is Required For Hindlimb Development, Katherine L. Rabicki

Electronic Thesis and Dissertation Repository

Mutations in chromatin organizer CTCF were identified in patients with intellectual disability and skeletal defects. Previous studies demonstrated that depletion of CTCF in murine limb mesenchyme results in apoptosis in the forelimb. The role of CTCF in the hindlimb, however, is unknown. My objective was to investigate effects of CTCF deletion on chondrogenesis and skeletal development in the hindlimb. In vitro wild-type micromass cultures demonstrate that chondrocyte gene expression is delayed in the hindlimb when compared to forelimbs. Embryonic Ctcf^Fl/Fl;Prx1Cre mice were investigated, and qRT-PCR and histology were performed on limb buds and long bones. Results show that …

Prenatal Programming Of Hepatic Glucose And Cholesterol Regulation In Male Rat Offspring By Chronic Intermittent Hypoxia, Waseem Iqbal

Electronic Thesis and Dissertation Repository

Obstructive sleep apnea (OSA) is a chronic disorder involving repetitive interruptions in breathing during sleep. Sufferers of OSA are exposed to chronic intermittent hypoxia (CIH), characterized by cyclical reductions in oxygen availability. A number of studies have established a link between OSA and various cardiovascular and metabolic comorbidities in adulthood, including hypertension, obesity, and type II diabetes. While the consequences of OSA in adults have been well described, the cross-generational impact of this condition and potential effects on fetal development are not known. Epidemiological and animal studies have demonstrated that physiological insults during pregnancy lead to diminished growth of offspring …