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Children with chronic inflammatory disease (CID) are at an increased risk for health complications including mental health issues, cancer, and cardiovascular disease. These complications have been linked to elevated levels of pro-inflammatory cytokines and lifestyle behaviours including low physical activity, and high sedentary time. Physical activity may represent a simple and effective strategy to modulate inflammation and subsequently improve health outcomes. However, the link between cytokines and movement behaviours in children with a CID remains poorly understood. Indeed, no studies to date have examined the link between a broad complement of inflammatory markers and patterns of movement behaviours in children with a CID. Therefore, the objectives of this study were to: (1) examine movement behaviours and inflammation in children with either cystic fibrosis (CF), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), and type 1 diabetes (T1DM), (2) examine movement behaviours and inflammation in children with a CID compared with healthy controls and (3) examine the association between movement behaviours and inflammation profiles in children with a CID. We hypothesized that (1) children with a CID will have comparable movement profiles and inflammation, (2) children with a CID will have lower physical activity levels and higher levels of pro-inflammatory cytokines relative to healthy counterparts, and (3) children with a CID who are more physically active and engage in less sedentary time will have less inflammation. Boys and girls with a CID and controls wore an ActiGraph GT3X accelerometer around the waist during waking hours for 7 days. Outcomes of interest included, sedentary time, time spent in light physical activity (LPA), moderate-to-vigorous PA (MVPA), and total PA (TPA), determined using Evenson cut-points. After one week a fasted blood sample was collected to determine serum cytokines (TNFα, IL-23, IL-1β, IL-12, IL-6, IL- 17, TGFβ, IL-10) by multiplex assays and C-reactive protein by enzyme linked immunosorbent assay. A total of 132 participants (47% girls; age: 13.3±2.8 years), including JIA (N=27), IBD (N=21), CF (N=14), T1DM (N=18) and healthy controls (N=52), completed the study. Physical activity and inflammatory profiles were comparable between CF, JIA, IBD and T1DM groups. Children with a CID participated in 13.3 fewer mins/day [95% confidence interval 6.9, 101.2] (MVPA (F(1,113)=11.015, p=0.001) of MVPA relative to healthy controls and had comparable cytokine profiles. Physical activity did not predict inflammation in children with a CID. However, we know that physical activity has many beneficial cardiorespiratory and mental health effects. As such, it is still of interest to uncover any potential effects movement behaviours may have on our immune system. / Thesis / Master of Science (MSc) / The purpose of this study was to assess how physical activity, sedentary time, and inflammation are associated. Inflammation is an important part of our immune system that protects us from infection and disease; however, when inflammation goes unchecked, it can cause serious chronic inflammatory disease. We were interested in understanding if children with a chronic inflammatory disease had different levels of physical activity and sedentary time, or different levels of inflammation than healthy children with no medical conditions. We were also interested in understanding if physical activity or sedentary time were related to levels of inflammation in children with a chronic disease. We asked boys and girls between 7 and 17 years old to visit our lab twice. Some of our participants had a medical condition, including chronic kidney disease, cystic fibrosis, juvenile idiopathic arthritis, or inflammatory bowel disease and type 1 diabetes. We also invited a group of children who had no medical condition to participate. During their first visit, we measured their weight, height, pubertal status and gave them a physical activity monitor to wear for 7 days before coming back for their second visit. At their second visit we took a small blood sample that we used to measure immune proteins called cytokines, these proteins act like messengers to tell the immune system what to do. Some of them make inflammation worse, and others help to bring down levels of inflammation. We found that children who had a chronic inflammatory disease participated in less physical activity but had similar levels of sedentary time compared with healthy children. We also found that there were no differences in inflammation between children with a chronic disease and healthy children. Lastly, we found that physical activity and sedentary time were not related to inflammation levels. Although we did not find a relationship between physical activity and inflammation, we know that physical activity has many beneficial cardiorespiratory and mental health effects. As such, it is still of interest to uncover any potential effects movement behaviours may have on health outcomes.

Rationale: The prevalence of obesity among individuals with chronic obstructive pulmonary disease (COPD) is increasing, which contributes to further ventilatory limitations, and compromised exercise capacity, and health-related quality of life (HRQOL) compared to COPD alone. Objective: To conduct a systematic review to evaluate the effects of exercise interventions on walking capacity, ventilatory parameters, anthropometrics and HRQOL in individuals with COPD and elevated weight. Methods: A search was conducted on March 16, 2018 of Embase, Medline, CINAHL, AMED and PsycINFO for controlled trials of exercise interventions, involving adults with any stage of severity and stability of COPD with concurrent obesity or overweight. Overall effects were determined with standardized (SMD) and weighted (WMD) mean difference, using Review Manager 5.3. Results: Nineteen studies with 1716 participants (BMI mean ± SD 28.2 ± 5.1 kg/m2) were included. Exercise interventions were effective in improving walking capacity measured by the 6-Minute Walk Test (6MWT), Endurance Shuttle Walk Test and Incremental Shuttle walk Test (12 studies, 1215 participants, SMD 0.25 (95% CI [0.06, 0.43]); p=0.01), fat-free mass index (2 studies, 285 participants, WMD 0.33 kg/m2 (95% CI [0.21, 0.46]); p<0.00001), St. George Respiratory Questionnaire (6 studies, 648 participants, WMD -7.49 points (95% CI [-13.01, -1.98]); p=0.008) and Chronic Respiratory Disease Questionnaire Dyspnea (5 studies, 478 participants, WMD 0.51 points (95% CI [0.00, 1.02]); p=0.05), Emotion (4 studies, 404 participants, WMD 0.28 points, 95% CI [0.03, 0.54]); p=0.03), and Mastery domains (4 studies, 404 participants, WMD 0.31 points (95% CI [0.02, 0.59]); p=0.03). There were no effects on ventilatory parameters or anthropometric measures. Conclusions: Exercise interventions were effective in improving walking capacity and HRQOL in individuals with COPD and elevated weight. There is an important opportunity to establish effective interventions to minimize the functional and health effects in this subset of the COPD population. / Thesis / Master of Health Sciences (MSc)

Chronic kidney disease (CKD) is a major cause of morbidity and mortality, affecting more than 10% of the world’s population. CKD is associated with excessive renal fibrosis, which leads to declining kidney function and eventual kidney failure. In CKD, glomerular mesangial cells (MC), resident fibroblasts and tubular epithelial cells undergo phenotypic activation and transition in response to profibrotic and proinflammatory cytokines such as transforming growth factor β1 (TGFβ1). These activated renal cells excessively produce extracellular matrix (ECM) proteins that replace functional renal tissue and lead to renal fibrosis. Caveolae are small omega-shaped invaginations of the plasma membrane that mediate signaling transduction events. Formation of caveolae require the protein caveolin-1 (cav-1). We have previously shown that the ability of MC to produce matrix proteins is dependent on cav-1 expression. Unfortunately, clinically targeting cav-1 within the kidneys, specifically within MC, is technically challenging and as of yet unfeasible. Thus, to better understand how cav-1 deletion is protective, we carried out a microarray screen comparing cav-1 wild-type (WT) and knockout (KO) MC. Here, we discovered significant up-regulation of a TGFβ superfamily inhibitory protein, follistatin (FST). FST specifically targets and neutralizes activin A (ActA) but not TGFβ1. TGFβ1 and ActA both belong to the TGFβ superfamily of cytokines and growth factors. While TGFβ1 itself is a known key mediator of renal fibrosis, therapies aimed at directly inhibiting TGFβ1 in kidney diseases have not been successful due to opposing profibrotic and anti-inflammatory effects. ActA has been shown to act as a strong profibrotic and proinflammatory agent in various organs, including the lungs and liver. We along with others have observed elevated levels of ActA within the kidneys and serum of mice and humans with CKD. Functionally, ActA has been shown to contribute to ECM production in the kidneys. Hence, we hypothesized that ActA inhibition through FST could prove beneficial in CKD. In this thesis, our first study elucidated a novel molecular pathway by which cav-1 regulates expression of the FST in MC. Our results indicate that FST is negatively regulated by cav-1 through a PI3K/PKC zeta/Sp1 transcriptional pathway. Our second study expands on these findings and tests whether exogenous FST administration protects against the progression of CKD in a surgical mouse model of CKD. Here, we discovered that FST acts as a reactive oxygen species (ROS) scavenger and that exogenous administration of FST protects against the development of CKD through the inhibition of renal fibrosis and oxidative stress. Lastly, our third study determined whether microRNAs (miRNAs) are implicated in post-transcriptionally regulating FST through cav-1 and whether these FST-targeting miRNAs can be utilized therapeutically to protect against the development and progression of CKD. Here, we determined that a FST-targeting miRNA, microRNA299a-5p, is significantly downregulated in cav-1 deficient MC, upregulated in vivo in a mouse model of CKD and that its inhibition, in vitro and in vivo protects against the accumulation of ECM proteins and renal fibrosis. These studies collectively suggest that FST is an effective therapeutic option for the management of CKD. / Thesis / Doctor of Philosophy (PhD) / Chronic kidney disease results from excessive fibrosis (scarring) within the kidneys. The goal of this thesis is to understand the molecular mechanisms involving the regulation of an antifibrotic protein, follistatin, in glomerular mesangial cells and to identify its therapeutic potential in chronic kidney disease. This thesis has identified that follistatin, an endogenous inhibitor of the profibrotic cytokine activin A, is regulated transcriptionally by Sp1 and post-transcriptionally by microRNA299a-5p. Furthermore, this thesis has demonstrated that exogenous recombinant follistatin administration protects against the progression of chronic kidney disease and that microRNA299a-5p targeting may be an alternative approach to block renal fibrosis. These studies collectively show that follistatin is an effective treatment for the management of chronic kidney disease.

Toxoplasma gondii is a protozoan parasite that causes life-threatening disease in congenitally infected infants and immunocompromised patients, such as those inflicted with AIDS. Toxoplasmic encephalitis (TE) is a common presenting condition in an AIDS infection. People become infected with T. gondii by ingesting tissue cysts in undercooked meats or by ingesting oocysts excreted by cats. Methylmercury (MeHg) is a well-documented neurotoxicant that accumulates in the brain and causes severe mental and visual dysfunction, including chronic encephalopathy. Consumption of contaminated fish, grains, and seeds are common sources of human exposure to methylmercury. Studies from our laboratory suggest that oral exposure to a single high dose of 20 mg/kg MeHg does not increase the susceptibility to acute toxoplasmosis in CBA/J mice. Therefore, we further investigated endpoints associated with immunotoxicity and neurotoxicity in 6-week old, female CBA/J mice exposed to both MeHg and T. gondii during a chronic T. gondii infection. We examined both single and multiple doses of MeHg exposure in a chronic parasitic infection model. In the single high dose study, four groups of six-week-old, female CBA/J mice were either fed 25 T. gondii tissue cysts of the ME-49 strain or given vehicle. Six weeks later, two out of the four groups (T. gondii and vehicle control) were orally gavaged with a single dose of 20 mg/kg body weight of MeHg and sacrificed seven days post exposure. Experiments from the multiple MeHg dose study were performed under similar conditions with the same number of groups and dosed by oral gavage with 8 mg/kg body weight of MeHg on days 0, 2,4,7,10,13. These mice were sacrificed on day 17 or 18 after initiating MeHg exposure. Flow cytometry following exposure to a single dose of MeHg in mice with a chronic T. gondii infection revealed significant changes (P < 0.05) within the T cell subpopulation percentages caused by exposure to MeHg. For example, the thymic CD4+CD8+ T cell subpopulations were increased (P <0.05). However, MeHg had no significant effect on the CD4+CD8-, CD4-CD8+, or non-T cell subpopulations in the spleen. Furthermore, MeHg increased splenic cellularity and spleen-to-body-weight ratios with or without a concurrent T. gondii infection. MeHg also caused a significant decrease in mouse body weight. There was a significant (P <0.05) increase in brain tissue cyst counts within the group exposed to both MeHg and T. gondii (16 ± 4, mean ± SE, n=7) versus T. gondii alone (4 ± 1, n=8). Histopathological examination demonstrated that the brain was affected, as lesions, gliosis, and meningitis were notable in mice given T. gondii. Exposure of mice to multiple doses of MeHg also resulted in effects on the immune system of CBA/J mice with and without chronic toxoplasmosis. Total cellularity and numbers of CD4+CD8+, CD4+CD8-, CD4-CD8+, and CD4-CD8- T-cell subpopulations show a marked decrease in number in the thymus, while total cellularity was also decreased in the spleen following concurrent exposure to T. gondii and MeHg. Flow cytometric examination of lymphocyte populations (CD4+ and CD8+ lymphocytes) in the spleen and thymus demonstrated differences from control in the groups exposed to T. gondii and MeHg. Histopathological examination did not reveal any significant lesions. The data from experiments in which single or multiple doses of MeHg were given to mice with a chronic T. gondii infection indicate that concurrent exposure, to both MeHg and T. gondii, dependent on dose and time of exposure had notable effects, especially on the immune system (Supported by NIH Grant F36GM20301). / Ph. D.

Objective: The purpose of the following study was to test the feasibility of using an ecological momentary assessment strategy during participation in water exercise. This assessment strategy was used to collect ratings of pain intensity level, affective status and self-efficacy for engaging in regular exercise prior to, during and following participation in water exercise for women with chronic pain. Design: Participants (N=15) completed six measures assessing physical activity level and reactions to physical activity and exercise participation and participated in elicitation interviews focused on their experiences with chronic pain and physical activity and exercise. Participants reported daily pain intensity levels, affect and self-efficacy each morning by phone and used cellular phones to report momentary ratings immediately following participation in water exercise for 6 weeks. Results: Participant profiles were developed to display patterns of pain intensity, affect and self-efficacy over the course of 6 weeks. Profiles indicated a variety of levels of exercise consistency in participants. Pain intensity, affect and self-efficacy varied over the course of an exercise event and revealed varied patterns across participants. Overall, momentary self-efficacy (M¹= 7.98, SD=1.65; M²= 8.29, SD=1.62; M³=8.45, SD=1.45) and affect mean ratings (M¹= 2.05, SD=1.42; M²= 2.76, SD=1.22; M³=3.02, SD=1.06) increased over the course of the exercise events while pain levels decreased from pre-exercise levels (M¹= 2.67, SD=2.30; M²= 1.85, SD=1.86; M³=1.95, SD=2.05). Elicitation interviews indicated themes related to the importance of enjoyment of exercise, social factors, and impact on pain level and overall physical condition. Final interviews provided information about the reactions of participants to the assessment strategy and offered insight into the acceptance of this approach for future studies of exercise behaviors. Conclusion: Overall, this approach to ecological momentary assessment of variables associated with exercise was acceptable to participants and revealed variable patterns of pain intensity, self-efficacy and affective state in relation to water-exercise engagement. / Ph. D.