The Role Of Timp3 In Microvascular Endothelial Cell-Extracellular Matrix Interaction And Regulation Of Microvascular Barrier Function, Nidhi Kulkarni

Electronic Thesis and Dissertation Repository

Pulmonary microvascular endothelial cell (PMVEC) interactions with the extracellular matrix (ECM) mediates PMVEC barrier function. Further, data suggests an association between decreased PMVEC-ECM interactions under proinflammatory conditions and PMVEC barrier dysfunction. Tissue inhibitor of metalloproteinases 3 (TIMP3) may also regulate barrier function, as PMVEC from Timp3^-/-mice show increased leak. Studies in the developing lung also showed TIMP3 regulating PMVEC-ECM interactions. Based on this, I hypothesized that TIMP3 maintains PMVEC barrier function by promoting PMVEC-ECM interactions.

Using the XperT-permeability assay, Timp3^-/-PMVEC demonstrated enhanced leak vs. WT PMVEC, particularly under proinflammatory conditions, and this was associated with decreased …

Detection And Quantification Of Cells Using Magnetic Particle Imaging And Magnetic Microspheres, Kierstin P. Melo

Electronic Thesis and Dissertation Repository

Magnetic particle imaging (MPI) is an emerging imaging modality that specifically detects superparamagnetic iron oxide nanoparticles (SPIOs). Our lab has shown that cell tracking with magnetic resonance imaging (MRI) has very high sensitivity, but low specificity and quantification of iron labeled cells is difficult. MPI cell tracking could overcome these limitations. A Momentum^TM MPI system was installed at Robarts in August 2019 and this is the first project to be completed using MPI. In Chapter 2 a series of in vitro experiments are reported which tested the repeatability and reproducibility of imaging SPIO labeled cell samples. There are no …

Improving Hydrid Pet/Mri Cardiovascular Imaging With Improved Hardware Design And Attenuation Correction Coefficient, Adam Helmy Farag

Electronic Thesis and Dissertation Repository

According to the World Health Organization (WHO) report in 2019, cardiovascular diseases (CVD) cause 52% of all illness-related deaths globally and are considered to be the second most common cause of death in Canada. CVD is also estimated to cost the Canadian economy about $21.2 billion in direct and indirect costs. With these figures, it is vital to develop the most effective and accurate methods and tools to diagnose accurately CVD and their causes. One of the promising tools for accurate diagnostic and therapeutic of CVD is the integrated Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) PET/MRI technology, …

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 …

Impact Of Graded Passive Cycling On Hemodynamics, Cerebral Blood Flow, And Heart Function In Healthy Adults And Septic Icu Patients, Jennifer Chen

Electronic Thesis and Dissertation Repository

Sepsis is a life-threatening dysregulation of host response to an infectious insult, which often leads to multi-organ failure. Sepsis survivors suffer from post-intensive care syndrome in part due to their prolonged bed rest and lack of mobility. Although early mobilization has been championed as a mechanism to counter the adverse effects associated with ICU immobility, due to sedation and mechanical ventilation, active early mobilization is not often administered in septic patients due to worries of hemodynamic instability and potential for inducing adverse events. Passive exercise is a mobilization modality that circumvents the need for patients to be conscious and participatory …

Chronic Neurological Impairment In Patients With Thrombotic Thrombocytopenic Purpura: Findings In Quantitative Mri, Jeffrey Hamilton

Electronic Thesis and Dissertation Repository

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening, microvascular blood disorder that affects approximately 5 people per million per year. The disorder is characterized by insufficient activity in ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats 13), which is an important enzyme in hemostasis because it prevents thrombosis. Along with blood clotting, other predominant symptoms are fever, anaemia, kidney failure, and neurological changes. Neurological changes may include confusion and decreased levels of consciousness, as well as depression and increased risk of seizures or stroke. However, little is known about the general pathology of these neurological changes and this forms …

The Impact Of Levodopa Administration On Learning From Short-Term And Long-Term Action Consequences: A Paradigm Validation., Masood Rezaei

Electronic Thesis and Dissertation Repository

Behavioral and neuroimaging studies have identified two valuation systems in the human brain for controlling behavior known as model-free (MF) and model-based (MB). MF is based on immediate evaluation and MB is based on long-term evaluation of the outcome of our decisions. Previous studies suggest that dopamine baseline activity may play an important role in the balance between the two systems and determine how they compete or interact in controlling our actions. The overarching aims of this study is to investigate the impact of levodopa administration on learning from immediate and long-term action consequences, and to dissociate the role of …

Vascular Stiffening And The Brain: Direct Measures Of Cerebrovascular Stiffness In Aging And Vasodilation, Christopher S. Balestrini

Electronic Thesis and Dissertation Repository

Dampening of pulsatile pressure waves within blood vessels is an essential feature of the arterial system. Vascular stiffening increases the speed and the pulsatile energy of the pressure wave, leaving low resistance organs like the brain vulnerable to microvascular mechanical damage. Due to access limitations, the effect of cerebrovascular stiffening on brain structure and neurological outcomes remains unknown. The purpose of this thesis was to assess the influence of vascular stiffening in peripheral arteries on white matter integrity (WMLv) (Chapter 2), obtain direct measures of cerebrovascular stiffness via phase contrast magnetic resonance imaging (PCMRI) (Chapter 3), and examine the impact …

Metabolic Syndrome Impairs Cerebrovascular Tone And Behaviour In Obese Zucker Rats, Brayden D. Halvorson

Electronic Thesis and Dissertation Repository

Metabolic syndrome is associated with cerebrovascular disease and cognitive impairment. We determined vascular reactivity in middle cerebral arteries (MCA), and performed cognitive testing using an operant conditioning chamber (OCC) and Morris Water Maze (MWM). Male obese Zucker rats (OZR) were used to test the hypothesis that the pro-inflammatory environment present in the OZR impairs cerebrovascular tone regulation and is associated with neuroinflammation of the white matter and cognitive impairment. Dilation of MCA following challenge with acetylcholine was blunted, whereas constrictor responses were enhanced. Learning was impaired in the MWM and a shift in swim strategy towards increased allocentric navigation was …

Examining Brain Connectivity And Reading Ability In Children, Alexandra M. Cross

Electronic Thesis and Dissertation Repository

In this thesis, I investigated the relationship between functional and structural connectivity and reading ability in children. Prior research has tended to use single word reading measures or composite measures, however this is problematic as reading is a complex skill relying on multiple subskills, such as decoding efficiency, sight word reading efficiency, reading comprehension, and rapid automatized naming. As a result, the multi-faceted relationship between brain connectivity and reading ability is not well understood. I aimed to address this issue by considering multiple reading subskills while examining the neural substrates of reading. In Chapter 2, I examined how individual differences …

An Approach For The In-Vivo Characterization Of Brain And Heart Inflammation In Duchenne Muscular Dystrophy, Joanne Tang

Electronic Thesis and Dissertation Repository

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin loss—notably within muscles and CNS neurons. DMD presents as cognitive weakness, progressive skeletal and cardiac muscle degeneration until pre-mature death from cardiac or respiratory failure. Innovative therapies improved life expectancy, but this is accompanied by increased late-onset heart failure and emergent cognitive degeneration. Thus, there is an increasing need to both better understand and track disease pathophysiology in the dystrophic heart and brain prior to onset of severe degenerative symptoms. Chronic inflammation is strongly associated with skeletal and cardiac muscle degeneration, however chronic neuroinflammation’s role is largely unknown in …

The Development Of Bacterial Magnetic Resonance Imaging For Microbiota Analyses, Sarah C. Donnelly

Electronic Thesis and Dissertation Repository

Current microbial analyses to assess either the commensal microbiota or microorganism infection and disease typically require ex vivo techniques that risk contamination and are not undertaken in real time. The possibilities for employing imaging techniques in the microbiology field is becoming more prominent as studies expand on the use of positron emission tomography, ultrasound and numerous microscopy techniques. However, magnetic resonance imaging (MRI), a non-invasive in vivo modality that can produce real-time results is falling behind. Here, we examined the feasibility of detecting bacteria using clinical field strength MRI. Commensal, probiotic and uropathogenic Escherichia coli were scanned by 3 Tesla …

Human Genetic Variation In Na+-Taurocholate Co-Transporting Polypeptide (Ntcp; Slc10a1) And Targeted Slc10a1 Disruption In Mice: Effects On Bile Acid And Rosuvastatin Transport, Laura E. Russell

Electronic Thesis and Dissertation Repository

Sodium-taurocholate co-transporting polypeptide (NTCP, SLC10A1) is the central bile acid uptake transporter on the basolateral membrane of hepatocytes. Pharmacological inhibition of NTCP is also being used to treat Hepatitis B and D, and NTCP transports a variety of drugs including cholesterol-lowering statins. Despite these crucial roles, limited knowledge exists regarding the effects of genetic variation in SLC10A1 on bile acid and rosuvastatin transport.

To address this, we characterized activity and protein expression of genetically variant SLC10A1 in vitro. Seven SLC10A1 genetic variants displayed robust reductions in NTCP-mediated transport of taurocholic acid and rosuvastatin and virtually absent NTCP protein …

A 3d Microvessel Model For The Study Of Endothelial Cell Transluminal Pillar Formation, Emma Kate Prescott

Electronic Thesis and Dissertation Repository

BACKGROUND: Endothelial cells (ECs) line the blood vessel lumen and respond to fluid shear stress. ECs are also responsible for initiating the formation of new blood vessels. These new vessels can form either by sprouting angiogenesis or intussusceptive, or splitting, angiogenesis. The latter is poorly understood but recent evidence suggests that intussusception occurs with altered blood flow. However, the biomechanical and biochemical mechanisms of intussusceptive angiogenesis remain largely unknown and in vitro models do not exist.

The purpose of this thesis was to develop a three-dimensional EC culture model capable of forming transluminal pillars, a key step in angiogenesis, and …

Tspo Pet Detects Acute Neuroinflammation But Not Diffuse Chronically Activated Mhcii Microglia In The Rat, Nassir Al-Khishman

Electronic Thesis and Dissertation Repository

Abstract

Background

Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) microglial activation in neurological diseases in vivo. The translocator protein (TSPO) is considered a sensitive target for imaging microglial activation with positron emission tomography (PET). This study aimed to test the ability of TSPO to detect WM microglial activation marked by major histocompatibility complex class II (MHCII) molecules in rat models of prodromal Alzheimer’s disease and acute subcortical stroke.

Methods

Fischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [¹⁸F]FEPPA PET and MRI to …

A Clinically Representative Rat Model Of Hip Hemiarthroplasty, Adam Dm Paish

Electronic Thesis and Dissertation Repository

Joint replacement is an increasingly common surgery with over 130,000 procedures performed annually in Canada. Although joint replacement surgery is highly successful, implants do not last a lifetime, and often have to be replaced via costly revision surgeries. Before innovations aimed at extending the life of implants are applied to the clinic, testing must be performed in animal models. Clinically representative small-animal models of joint replacement would be ideal in the initial stages of research and development, due to ease of handling and low costs, but few such models have been established in the literature. Thus, we describe the development …

A Hybrid Pet/Mri Brain Connectivity Approach For Improving Epilepsy Surgical Evaluation, Stefan E. Poirier

Electronic Thesis and Dissertation Repository

Hybrid PET/MRI can non-invasively improve epileptic focus (EF) localization prior to surgical resection in drug-resistant epilepsy (DRE), especially when MRI is negative. In this thesis, we developed an ¹⁸F-fluorodeoxyglucose (FDG) PET-guided diffusion tractography (PET/DTI) approach to assess white matter (WM) integrity in MRI-negative DRE and evaluated its potential impact on epilepsy surgical planning. To validate the potential of PET/MRI, we first evaluated the diagnostic competence of PET/MRI in DRE and found that PET/MRI provides similar diagnostic information as PET/CT (current clinical standard). For the PET/DTI approach, we used asymmetry index (AI) mapping of FDG-PET to guide WM fiber tractography …

Implications Of Long Non-Coding Rnas In The Pathogenesis Of Diabetic Retinopathy: A Novel Epigenetic Paradigm., Saumik Biswas

Electronic Thesis and Dissertation Repository

With the rising incidence of diabetic retinopathy (DR), there is an urgent need for novel therapies. Presently, several altered metabolic pathways have been implicated in the pathogenesis of DR. Recent advances in genomic technologies have identified considerable epigenetic alterations that also contribute to DR progression. Long non-coding RNAs (lncRNAs; >200 nucleotides), critical regulators of gene expression, are aberrantly expressed in DR and have not been comprehensively characterized. Our microarray analyses using human retinal endothelial cells (HRECs) revealed thousands of differentially expressed lncRNAs following high glucose (HG) exposure, with profound increases in the lncRNAs MALAT1 and HOTAIR. Using multiple techniques, …

Exploring The Effects Of Hemodialysis On Renal And Hepatic Blood Flow And Function Using Ct Perfusion Imaging, Raanan Marants

Electronic Thesis and Dissertation Repository

Hemodialysis (HD) is the most common form of renal replacement therapy for end-stage renal disease. However, patients develop complications that are driven by HD-induced circulatory stress from rapidly removing large fluid volumes during HD, making various vascular beds vulnerable to ischemia. By assessing how HD-induced circulatory stress affects different organs, it may be possible to characterize the mechanisms behind these complications and evaluate therapeutic interventions. This thesis aims to explore how HD affects renal and hepatic blood flow and function using CT perfusion imaging. For this work, patients received either standard or cooled HD first in a two-visit, crossover study …

Characterizing The Role Of The Microbiome In Kidney Stone Disease, Kaitlin F. Al

Electronic Thesis and Dissertation Repository

The goal of this thesis was to increase understanding of the role of the human microbiome in kidney stone disease, from stone nidus formation through to surgical stone treatment, using a combination of in vitro, in vivo, and human clinical investigations.

We first optimized our methods of sample collection for the use of such protocols in clinical studies involving urinary and gut microbiota investigations. We developed a novel method of fecal sampling that is amenable to study participants, inexpensive, and results in reliable downstream sequencing results.

We then utilized this sampling methodology in clinical investigations into the microbiota of …

Neurite Orientation Dispersion And Density Imaging In A Rodent Model Of Mild Traumatic Brain Injury, Patrick Mccunn

Electronic Thesis and Dissertation Repository

Mild traumatic brain injury (mTBI) has become a focal point within the medical community due to its increased prevalence in recent years. Unfortunately, there is currently no neuroimaging technique able to accurately diagnose and monitor mTBI in-vivo. One technique that has shown great promise is neurite orientation dispersion and density imaging (NODDI). NODDI is a diffusion MRI (dMRI) technique used to characterize microstructural complexity through the compartmental modelling of neural water fractions into Intra-neurite, Extra-neurite and CSF volume fractions. The overreaching theme of this thesis was to validate NODDI in a preclinical setting to then be applied to imaging …

Kinetic Analysis Of Dynamic Pet For Molecular, Functional And Physiological Characterization Of Diseases, Fiona Li

Electronic Thesis and Dissertation Repository

PET with targeted probes may better elucidate the molecular and functional basis of diseases. The widely used standardized uptake value from static imaging, however, cannot quantify the probe uptake processes like perfusion, permeability, binding to and disassociation (k₄) from target. The overarching thesis goal is to develop a model to enable kinetic analysis of dynamic imaging to separate these processes.

As perfusion delivery is not modelled in the current standard two tissue compartment (S2TC) model, I developed a flow modified two tissue compartment (F2TC) model that incorporates the blood flow effect. The model’s performances were investigated with simulation. …

Quantitative Dynamic Pet & Ct Perfusion For Cancer Imaging: Diagnosis & Monitoring Treatment Response, Dae-Myoung (Danny) Yang

Electronic Thesis and Dissertation Repository

Hybrid PET/CT imaging is a newer cancer imaging modality which allows contemporaneous PET metabolic/molecular and CT anatomical imaging during a single diagnostic session on a single device. However, current PET imaging has relied heavily on measuring the tracer accumulation in the tumour as a surrogate of the pathologic activity targeted by the tracer while CT is limited to measuring tumour size or visualizing tumour enhancement pattern, all of which lack sensitivity and specificity in detecting cancer and assessing treatment response. Therefore, it is critical to develop pharmacokinetic techniques for assessing the physiologic/molecular characteristics of tumours with clinical PET/CT scanners to …

Development And Evaluation Of A Heterogenous Virus-Like Particle (Vlp) Formulation To Achieve Hiv-1 Latency Reversal And Cure., Joshua P. Pankrac

Electronic Thesis and Dissertation Repository

HIV-1 is the etiological agent behind acquired immune deficiency syndrome (AIDS) – a chronic, life-threatening condition that compromises host immune function. After nearly four decades and despite ongoing global efforts, HIV-1 persists in nearly 38 million individuals worldwide. Of this population, only 60% have access to life-saving combination antiretroviral therapy (cART), clearly emphasizing the need to realize a cure. Unfortunately, the establishment of replication-competent provirus in resting CD4+ T lymphocytes represents a significant barrier to HIV-1 curative research. The viral reservoir is highly stable and has a half-life of ~44 months. Therefore, it is unlikely that infection will naturally exhaust …

A Novel System And Image Processing For Improving 3d Ultrasound-Guided Interventional Cancer Procedures, Derek J. Gillies

Electronic Thesis and Dissertation Repository

Image-guided medical interventions are diagnostic and therapeutic procedures that focus on minimizing surgical incisions for improving disease management and reducing patient burden relative to conventional techniques. Interventional approaches, such as biopsy, brachytherapy, and ablation procedures, have been used in the management of cancer for many anatomical regions, including the prostate and liver. Needles and needle-like tools are often used for achieving planned clinical outcomes, but the increased dependency on accurate targeting, guidance, and verification can limit the widespread adoption and clinical scope of these procedures. Image-guided interventions that incorporate 3D information intraoperatively have been shown to improve the accuracy and …

Investigating Pathways Associated With Intervertebral Disc Degeneration And Back Pain., Geoffrey J. Kerr

Electronic Thesis and Dissertation Repository

Lower back pain (LBP) is one of the most common conditions worldwide, yet, current therapeutics are limited to symptomatic relief and do not directly treat the underlying cause of pain. This is largely due to an incomplete understanding of the biological pathways and tissues involved in LBP. While many tissues appear to be involved, intervertebral disc (IVD) degeneration is believed to be a major contributor.

The main aim of this thesis was to characterize the role of two environmental risk factors, mechanical loading and obesity, in the initiation of IVD degeneration and associated pain using the mouse as a preclinical …

Structure And Function Of Asthma Evaluated Using Pulmonary Imaging, Rachel L. Eddy

Electronic Thesis and Dissertation Repository

Asthma has been understood to affect the airways in a spatially heterogeneous manner for over six decades. Computational models of the asthmatic lung have suggested that airway abnormalities are diffusely and randomly distributed throughout the lung, however these mechanisms have been challenging to measure in vivo using current clinical tools. Pulmonary structure and function are still clinically characterized by the forced expiratory volume in one-second (FEV₁) – a global measurement of airflow obstruction that is unable to capture the underlying regional heterogeneity that may be responsible for symptoms and disease worsening. In contrast, pulmonary magnetic resonance imaging (MRI) …

Assessment Of Intrinsic Hand Neuromuscular Physiology, Philemon Tsang

Electronic Thesis and Dissertation Repository

Alterations to the peripheral nervous system and neuromuscular physiology may impact hand function in a typical or clinical population, such as individuals with ulnar neuropathy. The mechanisms that influence these positive and negative changes are still not well understood. The three studies within my thesis aim to validate the reliability of decomposition-based quantitative electromyography (DQEMG) measurements and explore the changes in intrinsic hand neuromuscular physiology in a typical aging population and individuals recovering from a surgical intervention for severe ulnar neuropathy.

The purpose of the first study was to determine the test-retest reliability of near-fibre (NF) jiggle, a measure of …

The Effects Of Exercise On Cognition, Mobility, And Neuroimaging Outcomes In Older Adults Without Dementia, Narlon Cassio Boa Sorte Silva

Electronic Thesis and Dissertation Repository

Cognitive decline is increasing with the aging population and, at present, there is no effective pharmacologic treatment available. Exercise interventions may impart protection against cognitive decline. A novel exercise approach is multiple-modality exercise (MME; aerobic, resistance, and balance exercise) with mind-motor training. Mind-motor training is a promising intervention in the study of cognitive function. Combining MME with mind-motor training may improve or maintain cognition and provide prevention of dementia early in the course of cognitive decline. Individuals with subjective cognitive complaints (SCC) comprise an at-risk group early in the spectrum of cognitive decline that could be targeted for prevention. The …