Life Sciences Commons^™

Kiss1r Induces Human Mammary Epithelial Cell Invasiveness And Promotes Breast Cancer Cell Migration And Invasion Via Iqgap1, Donna Cvetkovic

Electronic Thesis and Dissertation Repository

Kisspeptins (KP), peptide products of the kisspeptin-1 (KISS1) gene are the endogenous ligands for a G protein-coupled receptor (KISS1R). KISS1 acts as a metastasis suppressor in numerous human cancers. However, recent studies have demonstrated that an increase in KISS1 and KISS1R expression in human breast tumors correlates with higher tumor grade and metastatic potential. We have previously shown that KP-10, the most potent KP, stimulates invasion of estrogen receptor (ER)-negative breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR). Here, I report that KP-10 treatment of the ER-negative non-malignant mammary epithelial MCF10A cells, or stable …

The Role Of Transforming Growth Factor Alpha In Osteoarthritis And Skeletal Development, Shirine E. Usmani

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is the most common joint disease and a major cause of physical disability, however no disease modifying treatments are available. To better understand the molecular mechanisms involved, my colleagues previously performed microarray studies on a surgical rodent model of OA. Transforming growth factor alpha (TGFa) was identified as a novel growth factor involved in cartilage degeneration and subsequent experiments revealed that it induced an OA-like phenotype in articular chondrocytes. These findings lead to the overarching hypothesis for my thesis: TGFa promotes OA.

I began by studying TGFa’s interaction with endothelin receptor A (ET(A)R) as this signaling system is …

Hypoxia-Induced Alterations In Skeletal Muscle Cell Respiration And Resveratrol As A Potential Pharmacological Intervention, Kathleen R. Belgrave

Electronic Thesis and Dissertation Repository

Using the C₂C₁₂ mouse muscle myoblast cell line, I sought to investigate the hypothesis that differentiation under hypoxia impairs muscle mitochondrial respiratory function irreversibly. Resveratrol (RSV) will increase expression of markers of mitochondrial biogenesis and reverse the hypoxia-induced depression of O₂ consumption rates. Hypoxia decreased oxygen consumption rates after five days of differentiation and after two days of normoxic recovery. This coincided with a hypoxia-induced decrease in protein levels of the NDUFB8 subunit of complex I of the electron transport chain and decreases in mRNA levels of mitochondrial biogenesis transcription factors, both of which could contribute …

Uncovering Dual Roles For Perk Signaling During Experimentally Induced Pancreatitis, Elena Fazio

Electronic Thesis and Dissertation Repository

Pancreatitis is characterized by inappropriate activation of digestive enzyme

precursors, or zymogens, local and systemic inflammation, dysregulation of

cellular calcium (Ca2+), and induction of the unfolded protein response (UPR).

The UPR consists of three distinct pathways all of which are activated during

pancreatitis. However, the molecular roles of each remain unclear. The

protein kinase RNA (PKR)-like ER kinase (PERK) pathway reduces general

protein translation by phosphorylating eIF2!, and is activated within minutes

of initiating pancreatic damage. Microarray analysis carried out by our lab

revealed robust upregulation of the PERK pathways members Activating

Transcription Factor (ATF) 3 and stanniocalcin (STC) 2. …

Identification And Characterization Of The Arabidopsis Homolog Of The Yeast Trex-2 Complex, Gang Tian

Electronic Thesis and Dissertation Repository

Nuclear pore complexes (NPCs) are vital to nuclear-cytoplasmic communication in eukaryotes. The yeast Thp1-Sac3-Cdc31-Sus1 complex, also known as the TREX-2 complex, is anchored to the NPC via the nucleoporin Nup1, and is essential for mRNA export. In this study, the Arabidopsis homolog of the yeast TREX-2 complex was discovered. Physical and functional evidence support the identification of the Arabidopsis orthologs of the yeast Thp1 and Nup1. Of three Sac3 Arabidopsis homologs, two are putative TREX-2 components. Surprisingly, none are required for mRNA export as is the yeast Sac3. Physical association with TREX-2 was observed for the two Cdc31 homologs, but …

Gait Variability Is An Independent Marker Of Frailty, Anam Islam

Electronic Thesis and Dissertation Repository

The objectives of this study were to 1) determine if high gait variability is associated with frailty; 2) test the inter-rater reliability of the Clinical Frailty Scale (CFS) and its concurrent validity against the Frailty Phenotype Index (FPI) in classifying frailty. Frailty status was determined by applying the FPI and CFS to the sample of 107 community-dwelling older adults. Inter-rater reliability of the CFS was assessed using kappa statistics. Mantel-Haenszel test for trends evaluated concurrent validity of the CFS against the FPI components. Quantitative gait variables were assessed with an electronic walkway. Multivariable linear regression analysis evaluated the outcome of …

Dynamics Of Fat And Lean Mass In Refuelling Migrant Passerines Measured Using Quantitative Magnetic Resonance, Lisa V. Kennedy

Electronic Thesis and Dissertation Repository

Although fat deposition during stopover in migrating passerine birds has been extensively studied, changes in lean mass during refuelling are not well understood. I used quantitative magnetic resonance (QMR) analysis to measure the deposition of fat and lean mass for both recaptured and single capture migrant passerines in spring and fall at Long Point, Ontario. Both the recapture analysis and single capture regression analysis indicated a substantial contribution of lean mass to overall increases in total body mass. Some of the variation in the relative deposition of fat and lean mass was explained by sex, age and season. I then …

The Developmental And Adaptive Role Of Mitogen Activated Protein Kinase Pathways During Preimplantation Development, Christine E. Bell

Electronic Thesis and Dissertation Repository

The preimplantation period of development represents the highest interval of embryonic loss throughout pregnancy. It is therefore imperative that we elucidate the mechanisms involved in regulating preimplantation embryonic responses to stress and that govern development. The MAPK pathways are involved in both responding to environmental stress and regulation of development throughout embryogenesis, and are therefore good candidates to study the mechanisms involved in preimplantation embryonic adaptation to stress and development. The preimplantation embryo culminates in the development of a fluid filled structure called the blastocyst. It is at this stage the first differentiation events occur and the trophectoderm (TE), which …

Overwintering Energetics Of Lepidoptera: The Effects Of Winter Warming And Thermal Variability., Caroline M. Williams

Electronic Thesis and Dissertation Repository

Winter temperatures are changing rapidly, and although winter warming reduces cold stress for overwintering ectotherms, temperature-mediated increases in metabolic rate can decrease fitness in dormant insects by increasing consumption of energy reserves. Increases in thermal variability also increase energetic demands, due to non-linear thermal response curves. My objective was to quantify the negative effects of winter warming and increases in thermal variability on a range of Lepidopteran species. As overwintering insects rely on lipid catabolism, accurate lipid measurement is central to my dissertation; so I first compared four methods of lipid quantification; concluding thin layer chromatography was the only method …

Morpho-Physiological Analysis Of Interneuronal Populations In The Rat Piriform Cortex Before And After Kindling Induced Epilepsy, Cezar Gavrilovici

Electronic Thesis and Dissertation Repository

The piriform cortex (PC) is involved in olfactory sensory processing, associative learning tasks and is highly seizurogenic. Understanding how interneurons participate in these behaviours, especially their contribution in epileptogenic mechanisms, is hampered by an incomplete understanding of their functional and morphological diversity. The hypothesis in this work is that kindling-induced epilepsy alters the firing properties of PC interneuronal populations. Altered/impaired interneuronal firing could lead to abnormal processing in the PC and epileptogenesis. Therefore it was important to first identify and describe interneuronal morpho-functional properties in the unkindled brain and then to assess the electrophysiological parameters following kindling.

Based on interneuronal …

Trace Metal Limitation And Its Role In Oxidative Stress Of Coral Algal Symbionts; Implications For Thermally Induced Coral Bleaching Events., Katrina Lynn Iglic

Electronic Thesis and Dissertation Repository

Coral bleaching, the process in which corals expel their photosynthetic symbionts (Genus Symbiodinium), is caused by high temperature and irradiance stress. The synergistic effect of each stressor is the generation of damaging reactive oxygen and nitrogen species (ROS and RNS), which are normally mitigated physiologically by antioxidant enzyme activity. Antioxidant enzymes require iron, copper, manganese and zinc in their structure and the limited nature of these trace metals in reef environments may enhance ROS production under elevated temperature and irradiance. The hypothesis tested within this thesis was that a limited availability of the trace metals Fe, Mn, Cu and …

Purine Transport And Metabolism In Microvascular Endothelial Cells, Derek B J Bone

Electronic Thesis and Dissertation Repository

The microvascular endothelium serves as the barrier between the blood and perfused tissues. Proper function of the endothelium is dependent on the ability of the endothelial cells to produce nitric oxide and form tight junctions between themselves. Dysfunction occurs when stresses overwhelm the endothelial cell, with oxidative stress being a leading cause. Intracellular metabolism of purine nucleosides and nucleobases has been implicated in the production of oxidative stress. Nucleosides (e.g. adenosine) and nucleobases (e.g. hypoxanthine) are moved across cell membranes by a specialized family of proteins called equilibrative nucleoside transporters (ENTs).

We characterized primary human cardiac microvascular endothelial cells (MVECs) …

Decoding Motor Intentions From Human Brain Activity, Jason P. Gallivan

Electronic Thesis and Dissertation Repository

“You read my mind.” Although this simple everyday expression implies ‘knowledge or understanding’ of another’s thinking, true ‘mind-reading’ capabilities implicitly seem constrained to the domains of Hollywood and science-fiction. In the field of sensorimotor neuroscience, however, significant progress in this area has come from mapping characteristic changes in brain activity that occur prior to an action being initiated. For instance, invasive neural recordings in non-human primates have significantly increased our understanding of how highly cognitive and abstract processes like intentions and decisions are represented in the brain by showing that it is possible to decode or ‘predict’ upcoming sensorimotor …

Mitochondrial Metabolic Suppression And Reactive Oxygen Species Production During Hypometabolism In Mammals, Jason Cl Brown

Electronic Thesis and Dissertation Repository

During hibernation, daily torpor, and fasting, mammals reduce metabolic rate (MR) up to 99%, 95%, and 30%, respectively, compared to resting levels. Mitochondrial metabolic suppression likely contributes to this MR reduction, and the first objective of this study was to determine the relative contributions of active, regulated inhibition and passive thermal effects as body temperature (T_b) falls, to mitochondrial metabolic suppression, and to examine the mechanisms involved using top-down elasticity analysis and novel statistical approach. The second objective of this study was to determine how mitochondrial metabolic suppression affects mitochondrial reactive oxygen species (ROS) production, a topic which …

Role Of Rac1 In Myocardial Tnf-Alpha Expression In Sepsis, Ting Zhang

Electronic Thesis and Dissertation Repository

Tumor necrosis factor-a (TNF-alpha) is a pro-inflammatory cytokine and its high levels of expression in the heart leads to cardiac dysfunction in sepsis. However, the underlying molecular mechanisms of regulating myocardial TNF-alpha expression are not fully understood. The aim of this thesis was to investigate the role of Rac1 in myocardial TNF-alpha expression and cardiac dysfunction during sepsis. Studies were performed using cultured neonatal cardiomyocytes and a mouse model of endotoxemia.

PI3K-mediated Rac1 activation is required for induction of TNF-alpha mRNA and protein expression in cardiomyocytes and cardiac dysfunction during endotoxemia. Rac1 promotes TNF-alpha mRNA expression via NADPH oxidase/ERK1/2 and …

On The Early Onset Of Vascular Stiffening And Sexual Dimorphism Of Sympathetic Control In The Spontaneously Hypertensive Rat, Louis Mattar

Electronic Thesis and Dissertation Repository

The purpose of this thesis was to explore the role of the sympathetic nervous system (SNS) in hindlimb vasomotor control during the development of hypertension (HT). Using an animal model of essential HT (the spontaneously hypertensive rat [SHR]) we demonstrated that neuropeptide Y (NPY) and the Y₁ receptor (Y₁R) play a greater role in modulating hindlimb hemodynamics in the early stages of HT compared to normotensive controls (Wistar Kyoto [WKY]). Hindlimb vascular mechanics (compliance [C] and viscoelasticity [K]) were assessed using a modified Windkessel model developed in our laboratory. The hindlimb mechanics did …

Cardiac Adaptation To Chronic Blockade Of Voltage-Gated, L-Type Calcium Channels In The Sarcolemma, Ji Zhou

Electronic Thesis and Dissertation Repository

L-type Ca²⁺ channels (dihydropyridine receptors, DHPRs) in the sarcolemma are essential to cardiac excitation-contraction (E-C) coupling. Thus, Ca²⁺ influx through DHPRs upon cardiomyocyte excitation triggers Ca²⁺ release from the sarcoplasmic reticulum (SR) through ryanodine receptors (RyRs) to initiate myofilament activation and muscle contraction. Muscle relaxation occurs upon sequestration of Ca²⁺ back into the SR lumen by sarco/endoplasmic reticulum calcium-ATPase (SERCA) in the SR. As a treatment option for hypertension, long-term use of DHPR blockers is associated with increased risk of heart failure; underlying mechanisms are unknown. This research used male Wistar rats treated with verapamil (subcutaneously, …

The Roles Of Nitric Oxide Synthases (Nos) In Endochondral Bone Formation, Qian Yan

Electronic Thesis and Dissertation Repository

Longitudinal growth of endochondral bones is controlled by the cartilage growth plate. Chondrocyte proliferation and hypertrophy, vascular invasion, formation of ossification centers and cartilage replacement by bone tissue are all important processes required for normal growth. These biological processes have to be tightly regulated or disturbances will lead to skeletal diseases. A large number of genes, growth factors and hormones have been implicated in the regulation of growth plate biology, however, less is known about the intracellular signaling pathways involved. Nitric oxide (NO) has been identified as a regulator of cellular proliferation, differentiation, migration, survival and metabolism in multiple cell …