The influenza virus has a large impact on global health; however, it is difficult to formulate vaccines and influenza therapies that are effective against influenza. The influenza virus mutates rapidly, has the ability to emerge as novel strains with pandemic potential and can quickly become resistant to any given drug. Therefore, the generation of novel anti-influenza therapeutics that are effective against multiple strains would be highly beneficial. To date, the majority of anti-influenza research has focused on targeting specific components of the virus in order to interfere with its replication. However, it has been proposed that host proteins and signaling pathways may be essential components to viral replication and could also become novel anti-influenza drug targets. Therefore, this study utilized a large proteomic screen to identify host proteins that were up- and down-regulated in response to influenza infection. Collectively, these proteins clustered into five specific cell pathways and processes including interferon signaling, purine metabolism, cell death, ubiquitin-like signaling and mitochondrial oxidoreductases. Overall, this project identified potential novel anti-influenza targets in primary airway epithelial cells. / May 2015

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Includes bibliographical references (p. 85-103).

Thesis (D.M.S.)--Uppsala University, 2000. / "Acta Universitatis Upsaliensis." Extra abstract sheet inserted. Includes bibliographical references (p. 50-57).

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Background and Rationale: Asthma and overweight are public health concerns. Lifestyle, including dietary and activity patterns, is associated with overweight and asthma. Moreover, an association between these two diseases has been described. Yet, few studies have considered these associations longitudinally in youth. Methods: Based on data from the 1995 Manitoba Birth Prospective Cohort (n=723, 404 [55.9%] boys), we designed a series of studies to address the question: “Do obesity and related lifestyle behaviours influence asthma and airway hyperresponsivess (AHR) outcomes in children?” Following protocol for a mixed methods sequential explanatory design study, we first considered this research question using quantitative methods. Exposure variables included weight status (body mass index (BMI); BMI z-scores; normal weight vs. overweight), diet, physical activity and screen time. Outcome variables included asthma and AHR at 8-10 years old and at 12-13 years old. Quantitative findings provided direction for the qualitative investigations. That is, we sought to further explain some of the quantitative findings using qualitative methods. For the qualitative portion of this dissertation, 15-16 year old youth were purposively selected (Winnipeg residency, asthma status, gender) from the 1995 Manitoba Prospective Birth Cohort. Due to recruitment challenges, participation was supplemented with youth from the Canadian Asthma Primary Prevention Study, using the same purposive selection criteria. Quantitative Results: Overweight at 12-13 years old was associated with a two-fold increased odds of persistent asthma in girls. In contrast, boys within the highest BMI quartile at 8-10 years old were nearly twice as likely to have remittent asthma at 12-13 years old. High vegetable intake was protective against allergic asthma and moderate-to-severe AHR by 50% and 42%, respectively. High screen time at 8-10 years old, particularly amongst overweight youth, was associated with an increased odds of asthma, but not AHR at 8-10 years and 12-13 years; there were no associations between physical activity, asthma and AHR. Qualitative Results: Youth spoke of asthma as a condition that neither limits physical activity, nor is an excuse for refraining from physical activity. Conclusions: Modest evidence that some quantitatively-measured weight and related lifestyle behaviours during the pubertal years is associated with asthma. Yet, qualitative data suggest that youth with asthma believe that physical activity is achievable despite their condition, although some describe that asthma interferes with physical activity.

Caveolin-1 is a marker protein for caveolae and can be a regulator of intracellular signaling pathways that contribute to the pathogenesis of human diseases. In the present study, the structural and functional changes of the lung in caveolin-1 null mice (Cav-1-/-) were assessed. Respiratory mechanics, measured using a small animal ventilator, revealed heightened central airway resistance (Rn), tissue resistance (G) and tissue elastance (H) in response to inhaled methacholine. The respiratory hyperreactivity is associated with increased collagen deposition around central and peripheral airways in Cav-1-/- mice; however, no difference was found in smooth muscle α-actin quantity between mouse strains. Similar to our in vivo findings, tracheal rings from Cav-1-/- mice mounted on an isometric wire myograph exhibited enhanced maximum active contractile force without a change in sensitivity (EC50) to methacholine. Rho kinase (ROCK1/2), protein kinase C (PKC) and extracellular signal regulated kinase 1/2 (ERK1/2) signaling were assessed as possible sources of the enhanced airway reactivity observed in Cav-1-/- mice. Inhibition of Rho kinase markedly blunted in vivo lung function responses (Rn) and (G) and ex vivo smooth muscle responses to methacholine. In fact, inhibition of Rho kinase completely eliminated any difference in response between mouse strains. Thus, our data indicate that Cav-1 may regulate mechanisms, such as Rho/Rho kinase signaling, that determine airway smooth muscle contraction and airway fibrosis; thus, it could be an important regulator of airway biology and physiology in health and disease.

Caveolin-1 is a marker protein for caveolae and can be a regulator of intracellular signaling pathways that contribute to the pathogenesis of human diseases. In the present study, the structural and functional changes of the lung in caveolin-1 null mice (Cav-1-/-) were assessed. Respiratory mechanics, measured using a small animal ventilator, revealed heightened central airway resistance (Rn), tissue resistance (G) and tissue elastance (H) in response to inhaled methacholine. The respiratory hyperreactivity is associated with increased collagen deposition around central and peripheral airways in Cav-1-/- mice; however, no difference was found in smooth muscle α-actin quantity between mouse strains. Similar to our in vivo findings, tracheal rings from Cav-1-/- mice mounted on an isometric wire myograph exhibited enhanced maximum active contractile force without a change in sensitivity (EC50) to methacholine. Rho kinase (ROCK1/2), protein kinase C (PKC) and extracellular signal regulated kinase 1/2 (ERK1/2) signaling were assessed as possible sources of the enhanced airway reactivity observed in Cav-1-/- mice. Inhibition of Rho kinase markedly blunted in vivo lung function responses (Rn) and (G) and ex vivo smooth muscle responses to methacholine. In fact, inhibition of Rho kinase completely eliminated any difference in response between mouse strains. Thus, our data indicate that Cav-1 may regulate mechanisms, such as Rho/Rho kinase signaling, that determine airway smooth muscle contraction and airway fibrosis; thus, it could be an important regulator of airway biology and physiology in health and disease.