Biomedical Physiology and Kinesiology - Theses, Dissertations, and other Required Graduate Degree Essays

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Mathematical modelling of mammalian target of rapamycin following leucine ingestion

Author: 
Date created: 
2018-07-26
Abstract: 

Nutritional and hormonal factors primarily dictate skeletal muscle protein synthesis rates but how the whole-body dynamics of these factors mediate the cell signalling underlying protein translation is poorly understood. The purpose of my research was to develop and analyze a mathematical model of protein translational signalling in human skeletal muscle following leucine ingestion. The model incorporated the signalling proteins involved in the control of protein translation (e.g., IR/PI3K/AKT/mTOR) and was constructed by modifying amalgamated models of mTOR signalling and skeletal-muscle leucine kinetics. Initial model outputs agreed with tracer measurements and biopsy-based signalling data but failed to accurately simulate phospho-p70S6K. I proposed three hypotheses of p70S6K control and developed an expanded mTOR signalling network to improve the phospho-p70S6K kinetics. All proposed modifications failed to noticeably improve the accuracy of phospho-p70S6K simulations. My model represents a working hypothesis of protein translational control in skeletal muscle by nutritional and hormonal factors.

Document type: 
Thesis
File(s): 
Senior supervisor: 
David Clarke
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Healthy at 100: Genetic factors and phenotypes associated with healthy aging and longevity

Author: 
Date created: 
2018-07-27
Abstract: 

Background. Healthy aging and longevity are distinct phenotypes that describe an individual’s health span and life span, respectively. Both are complex phenotypes that are influenced by lifestyle, environment, and genetics. Using Super-Seniors, individuals aged 85 years and older and free of major chronic disease, and mid-life controls, I investigated whether Super-Seniors have an overall decreased genetic susceptibility and increased resilience to age- related diseases. Results. Using lifestyle, health, and genetic data, I compared the phenotypic and genetic characteristics of Super-Seniors to mid-life controls. Super-Seniors performed well on geriatric tests when compared to other long-lived populations, and an even more select group of Super-Seniors who survived 10 years after their initial recruitment still exhibited high function and good health. Super-Senior parents also exceeded the life expectancy for their era by a decade, and female Super-Seniors had an older age of last fertility, and were more likely to have had a child at ≥40 years.Exome sequencing of two centenarian brothers suggested that long-lived individuals do not carry a decreased burden of common complex disease variants. Instead, protective buffering variants that attenuate the effects of deleterious variants may play a role in healthy aging. In an analysis of buffering candidates, Super-Seniors were less likely than controls to carry an APOEε4 allele or a haptoglobin HP2 allele, and I identified 3 potential gene-gene interactions. In a network analysis of candidate buffering genes, lipid and cholesterol metabolism was a common theme. Further exploring the potential for protective factors in the Super-Seniors, I looked for evidence of allele-specific expression among disease genes, however no differences between groups were found. Conclusions. Super-Seniors are cognitively and physically high functioning individuals who have evaded major age-related chronic diseases into old age. The familiality of long lifespan of the parents of Super-Seniors supports the hypothesis that heritable factors contribute to this desirable phenotype. Although Super-Seniors did not appear to carry a decreased burden of disease-associated variants, there was some evidence that they may carry protective factors. The Super-Seniors are a phenotypically healthy group in which to look for further genetic markers of healthy aging and longevity.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Angela Brooks-Wilson
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) Ph.D.

Technical apparel performance for women during rest and exercise in a cold environment

Author: 
Peer reviewed: 
No, item is not peer reviewed.
Date created: 
2018-04-16
Abstract: 

At an ambient temperature of -4°C, in 3 trials, while wearing 1 of 3 differently designed jackets, 10 women ran for 15 min, rested for 10 min and ran again for 15 min. They were measured for body temperatures, heat flux and clothing microclimate conditions plus they gave thermal comfort votes. It was hypothesized for jackets that varied in the placement of their regional fabric thermal resistance either in an inverse proportion (Jacket 1) or in a direct proportion (Jacket 2) to previously reported TSK (Fournet et al., 2013) that they would elicit different physiological responses and thermal comfort votes than a Control Jacket of consistent overall fabric thermal resistance, and, 2) that Jacket 1 would give better physiological responses and thermal comfort votes than Jacket 2. Results gave physiological responses that mostly followed as expected from the overlying fabric thermal resistance. Differing core temperature and regional physiological responses were evident between the 3 jackets but few results supported Jacket 1 had better physiological responses than Jacket 2. Jacket 1 gave significantly better thermal comfort votes than Jacket 2 and the Control Jacket in the first 15 min of exercise but the effects of the differing jacket designs were not evident in the second rest period and in the second 15 min exercise period. In conclusion, designing jackets with varied placement of regional fabric thermal resistance has potential to improve winter jacket performance.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Matthew White
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Gaze training to improve mobility problems caused by glaucoma-related visual deficits

Date created: 
2018-04-23
Abstract: 

People with glaucoma collide with objects and fall more frequently than normally sighted individuals. Glaucoma-related visual field loss disrupts appropriate gaze behaviour, which is necessary for foot placement and route selection through cluttered environments. Thus, we developed a gaze training intervention to modify gaze behaviour. We taught (2, 1-hr sessions) older adults with glaucoma (n = 10) appropriate scanning and task-specific gaze strategies. To assess its effectiveness, participants performed a precision walking and obstacle avoidance task before and one-week after training. After training, participants shifted their gaze away from targets later relative to stepping on them and decreased foot-placement error and error variability. In the obstacle avoidance task, participants made more fixations before walking, shifted their gaze away from obstacles earlier with respect to crossing them, and had fewer obstacle collisions. Our results suggest that gaze is modifiable in older adults with glaucoma, and that gaze training may improve mobility.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dan Marigold
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Brain vital signs: Auditory to visual translation

Date created: 
2018-04-20
Abstract: 

An objective measure is greatly needed to monitor the impacts of injury or disease on our brain health. In order to provide such a measure, the brain vital sign framework utilizes an established, non-invasive, and physiology-based technology, Electroencephalogram (EEG), along with a rapid auditory sequence used to elicit and assess specific markers of cognitive function (marked by event-related potentials (ERPs)). To date, applications for brain vital signs have included evaluation of cognitive function in healthy and patient populations. To expand the applications, this study aims to translate the established rapid auditory sequence to a visual based assessment. The objectives are to: 1) demonstrate the viability of visual brain vital signs assessment and 2) examine the differences between the two modalities. EEG data was collected in 30 healthy adults (33±14yrs) and analyzed at central electrodes. Similar to the interlaced auditory sequence, the visual sequence utilized an oddball paradigm (standard vs. deviant stimuli) to evoke a sensory (N100) and attention (P300) response, and a word pair paradigm (congruent vs. incongruent stimuli) to evoke a semantic language response (N400). Comparison of mean amplitudes between stimuli revealed the targeted ERPs were successfully evoked in the visual modality at a group-level as expected (N100: p < 0.001; P300: p < 0.0001; N400: p = 0.0105). Attention processing (P300) was found to be the most transferrable across modalities, with no group-level differences and correlated peak amplitudes (rho = 0.7, p =0.0001) across individuals. Auditory P300 latencies were shorter than visual (p < 0.0001) but normalization and correlation (r =0.5, p = 0.0033) implied a potential systematic difference across modalities. Reduced auditory N400 amplitudes compared to visual (p = 0.0061) paired with normalization and correlation across individuals (r = 0.6, p = 0.0012), also revealed potential systematic modality differences between reading and listening language comprehension. This study provides initial understanding of the relationship between the visual and auditory sequences, while importantly establishing a visual sequence within the brain vital signs framework as a potential translational tool to monitor brain health over the human lifespan in broader populations, such as those with hearing impairments, congenital or due to injury or aging.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Stephen Robinovitch
Ryan D'Arcy
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Physiological and pharmacological switches combine to uniquely modulate the most common cardiac sodium channel mutant, E1784K

Date created: 
2018-03-08
Abstract: 

The SCN5a gene encodes the cardiac voltage-gated sodium channel (NaV1.5) mainly expressed in cardiac muscle cells. The inward sodium current (INa) conducted by NaV1.5 triggers depolarization in the cardiac action potential. Mutations in SCN5a predominantly give rise to Long-QT syndrome 3 (LQT3), Brugada syndrome 1 (BrS1), and their overlapping phenotypes (mixed syndrome). The most common SCN5a mutation, expressed as E1784K in the NaV1.5 C-terminal domain (CTD), mainly displays LQT3 and sometimes mixed syndromes. E1784K causes mixed channel defects by decreasing the inward peak INa and increasing late INa, thought to underlie BrS1 and LQT3 pathogeneses, respectively. Very little is known, however, on how physiological and pharmacological switches modulate E1784K channel properties. These triggers may often govern phenotypes in SCN5a mutation carriers. The goal of my thesis is to study how exercise-related physiological triggers and pharmacological agents modulate E1784K ion channel properties. I used the whole-cell patch clamp technique to study elevated temperature, elevated cytosolic calcium, and their combined effects with ranolazine, on E1784K. Ranolazine is an antianginal drug with preferential selectivity for blocking late INa versus peak INa. My main results show that E1784K is uniquely altered by the triggers studied, compared to other NaV1.5 mutants: (1) Elevated temperature augments late INa in E1784K. (2) Elevated cytosolic calcium, which correlates with exercise-ameliorated LQT3, effectively blocks late INa in most NaV1.5 mutants. However, E1784K is resistant to the native calcium-induced block on late INa. (3) When temperature and cytosolic calcium are combined, they decrease ranolazine efficacy to suppress late INa in E1784K. The calcium-sensitivity in E1784K is clearly affected due to the mutant-induced instability in the CTD, which may cause a steric clash between the channel and ranolazine. To predict E1784K effects on arrhythmogenesis, I simulated a dynamic action potential model to account for the frequency-dependent elevations in cytosolic calcium. Alternans is observed at high heart rates in E1784K and is exacerbated by febrile temperatures and ranolazine. This work demonstrates the importance of personalized medicine since NaV1.5 mutants like E1784K display unique sensitivity to physiological triggers that potentially govern antiarrhythmic efficacy.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Peter Ruben
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.

Physiological and anthropometric predictors of mountain ultra marathon performance

Date created: 
2017-12-13
Abstract: 

There is yet to be a resolution of the determinants of mountain ultra marathon (MUM) performance. The aim of this thesis was to contribute to resolving these determinants by measuring aerobic, anaerobic and anthropometric metrics and assessing their association to performance in a 50 km MUM race. It was hypothesized for MUM runners with high aerobic power that greater anaerobic capacity, greater lower limb girths, greater surface-area-to-mass, lower endomorphy and lower body fat percentage (BF%) would give better MUM performance. Thirty-four healthy participants volunteered for this study and were measured for their aerobic power, critical velocity (CV), anaerobic running capacity (D’), Wingate Anaerobic test (WAnT) power, and anthropometric variables. For these MUM runners with an aerobic capacity of 57.8±6.2 ml•min-1•kg-1 a greater CV predicted a faster finishing time in the MUM race (R2=0.75, p<0.001, n=12), while WAnT (r=-0.59, p<0.01, n=29) and mass-adjusted surface area (r=-0.35, p<0.05, n=34) was correlated to finishing time. Predictors of hill climb times included CV, body fat percentage and endomorphy (0.15

Document type: 
Thesis
File(s): 
Senior supervisor: 
Matthew White
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Proton modulation of residue E1784 and its regulation of fast inactivation

Date created: 
2017-12-14
Abstract: 

The cardiac voltage-gated sodium channel, NaV1.5, is responsible for the phase 0 depolarization of the ventricular cardiomyocyte action potential. NaV1.5 activates in response to depolarization, passes a transient inward sodium current, and then inactivates within milliseconds. Mutants in NaV1.5 that decrease the peak sodium transient cause Brugada syndrome and those that increase the fraction of channels that fail to inactivate cause long QT syndrome type 3 (LQT3). Some mutants both decrease the peak current and increase the non-inactivating current, leading to an overlapping phenotype of Brugada syndrome and LQT3. Of these mutants, E1784K in the proximal C-terminus is the most prevalent. The E1784K mutant alters channel opening, fast inactivation, and slow inactivation, but the exact mechanism by which it does so is unknown. Nor is it known why patients may experience normal heart function for many years before appearance of an arrhythmia. In these studies, the cut-open voltage-clamp technique is used to record NaV1.5 currents and voltage-sensor fluorescence from residue 1784 mutants expressed in Xenopus laevis oocytes. Experiments are conducted with extracellular pH between 7.4 and 4.0. Based on these data, a novel model of the voltage-gated sodium channel is constructed. The following data show that: (1) the E1784K mutant-dependent loss-of-function and gain-of-function effects are preferentially exacerbated by decreases in extracellular pH; (2) the E1784K mutant disrupts channel fast inactivation; (3) the mutant-dependent effects on channel conductance and the preferential effects of decreasing extracellular pH are due to altered channel fast inactivation; (4) non-inactivating sodium current is conferred by a positive charge at residue 1784. These data provide mechanistic insight into how a single mutant may cause multiple disease phenotypes, paving the way for future therapeutic research.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Peter Ruben
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Dissertation) Ph.D.

The beta-2 adrenergic receptor agonist fenoterol triggers arrhythmogenesis in isolated mouse ventricular cardiomyocytes.

Date created: 
2017-12-15
Abstract: 

Since the discovery of the role of Ca2+ in cardiac contractions, it has been clear that many cardiovascular disorders, specifically cardiac arrhythmias are due to irregularities in Ca2+ cycling. We hypothesize that fenoterol, a beta-2 adrenergic receptor agonist, is responsible for inducing abnormal Ca2+ release events that can lead to full cardiac arrhythmias. Ca2+ release events such as sparks, waves, and transients were studied using resonant confocal microscopy in isolated mouse ventricular cardiomyocytes with cumulative concentrations of fenoterol. Fenoterol application in clinically relevant doses can trigger potentially serious cardiac arrhythmias. The data showed that at low fenoterol concentrations, the frequency of Ca2+ sparks and waves were increased and caused Ca2+ oscillations during transients, all of which are indicators of arrhythmogenic Ca2+ activity, via the PKA-mediated pathway. At high concentrations, fenoterol lost its specificity and triggered beta-1AR, activating CaMKII, also resulting in more Ca2+ sparks and wave events and causing oscillations during field-stimulated elicited transients.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Glen Tibbits
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.

Using an activator of hERG (RPR-260245) in a model of acquired and inherited Long QT syndrome type 2

Author: 
Date created: 
2017-07-17
Abstract: 

The human ether-a-go-go related gene (hERG) channel is the molecular correlate of the rapid delayed rectifier current (IKr); its dysfunction causes Long QT syndrome type II (LQT II). RPR-260245 (RPR) is an activator of hERG that increases hERG current by slowing deactivation. Thus, it represents a potential treatment strategy for LQT. However, only few studies have addressed its impact on cardiac physiology. We used electrophysiology techniques in Xenopus Laevis oocytes and optical mapping in induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) to test the effects of RPR on hERG and on the cardiac action potential. We show that RPR has little effect on the cardiac AP in WT iPSC-CMs but demonstrate a partial rescue in our model of acquired LQT (aLQT) under dofetilide block and a partial rescue in our model of LQT II. Finally, RPR significantly increases protective hERG current, especially in instances of the R56Q mutation.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Glen Tibbits
Thomas Claydon
Department: 
Science: Department of Biomedical Physiology and Kinesiology
Thesis type: 
(Thesis) M.Sc.