Mast cells (MC) are present in nearly all tissues in the body and participate in many physiological processes including allergy, tissue remodelling, fibrosis, angiogenesis, and autoimmunity. They can be activated by many stimuli, including allergic and innate immune stimulation. When activated, MC release mediators through which they can regulate inflammatory processes. Recently, we have discovered that rat and human MC express the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the gene responsible for Cystic Fibrosis (CF). We showed that CFTR had functional activity in MC and its expression was differentially regulated by IFNg. In this thesis, we compared CFTR expression between MC and epithelial cells (EC) by Western blot analysis and found that CFTR expression in MC is similar to that in EC, but there are some differences which suggest either glycosylation or post-transcriptional/translational differences between MC and EC. We also explored the role of CFTR in human MC secretion from various cellular compartments, in response to various stimuli. When we blocked CFTR using pharmacological inhibitors, there was an inhibition of cAMP-dependent Cl- flux. Our data also shows that CFTR pharmacological inhibition had no effect on IgE/anti-IgE-mediated b-hexosaminidase or eicosanoid release from MC. When we stimulated MC with either IgE/anti-IgE or the adenosine receptor agonist NECA (3 uM) for 24h in the presence of CFTR inhibitors, secretion of several mediators appeared to be dysregulated including IL-8, MIF, IL-13, IL-16, PAI-1 and CCL1. To add to these findings, we also used short hairpin RNA (shRNA) to reduce CFTR expression in MC. CFTR deficient MC were unresponsive to NECA and showed reduced constitutive IL-6 secretion. Finally, we cultured MC from CF and non-CF donor peripheral blood progenitors and compared several phenotypic and functional aspects of the cells. We saw no difference in growth, protease content and surface marker expression between CF and non-CF MC, but stimulation of the cells with IgE/anti-IgE or Pseudomonas aeruginosa appeared to differentially induce cytokine synthesis and secretion from CF and non-CF MC. These findings suggest that MC function is dysregulated in CF and that CF MC may be involved in the pathophysiology of CF. / Experimental Medicine

Thesis (Ph. D.)--Case Western Reserve University, 2008. / [School of Medicine] Department of Pharmacology. Includes bibliographical references.

Thesis (M.Med.Sc.)--University of Western Australia, 2007.

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2005. / Includes bibliographical references (leaves 78-89). Also available in electronic version.

Thesis (Ph. D.)--University of Missouri-Columbia, 2005. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on October 18, 2007) Vita. Includes bibliographical references.

Class of 2006 Abstract / Objectives: To develop a new equation to predict creatinine clearance specific for cystic fibrosis patients. Methods: A literature review was performed to capture data on the daily creatinine excretion in CF patients in relation to age, weight, height, and other physiologic variables. Nonlinear mixed effect modeling was then used to develop an equation to estimate creatinine clearance using individual covariates. The performance of the new equation developed was compared to the Cockcroft and Gault method in a CF population (age > 16 years). Results: A database of individual patient data from a previously published study of 19 patients was created. Significant covariates for model development included actual body weight, sex, and serum creatinine. The final candidate model was: 5.62× ABW0.67 CrCl = sCr(mg / dl) × 0.649( female) Conclusions: The results of the mean absolute error and root mean squared error calculations show that the new equation resulted in less bias and better precision than Cockcroft-Gault, Jeliffe I, and Jeliffe II based on the limited data available. However, these conclusions are limited in that the only evaluation data available was the same data that was used for model development.

Only in recent years have diagnostic and therapeutic advances lengthened the life expectancy for patients who have cystic fibrosis sufficiently to allow some of them to live into adulthood. Health care professionals have been focusing on survival issues and are only recently beginning to look at quality of life issues, such as sexuality, of these patients. The purpose of the study was to create a sexual profile of adults with cystic fibrosis which would describe their sexuality and sexual concerns. A questionnaire was developed and sent to all of the adult cystic fibrosis patients (19 years of age and older) in British Columbia (50 patients), all of whom attend the Shaughnessy Hospital Adult CF Clinic in Vancouver. The 62% response rate provided data for the sexual profile which indicated that 90% of the respondents were sexually active. Only a small number of subjects reported sexual difficulties in their relationships. Concerns about the impact of CF on their sexuality included: the effect of the potentially limited lifespan on their relationships, practical considerations such as fatigue and coughing during sexual activity, and poor body image. A major issue for CF males is that most of them are infertile due to CF. How and when men should be told about this issue was an important question for the CF Clinic staff. Responses indicated that men thought they should find out from either the physician in the pediatric CF clinic or the physician in the adult CF clinic. Furthermore, 100% of the men suggested that this issue be discussed with males before the age of 19 years. Limitations and recommendations of the research are discussed. A major recommendation is for physicians and other health care professionals in CF clinics to give patients the opportunity to discuss sexual issues. / Education, Faculty of / Educational and Counselling Psychology, and Special Education (ECPS), Department of / Graduate

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